Tetrazolyl-phenyl acetamide glucokinase activators

ABSTRACT

Tetrazolyl-phenyl acetamides are active as glucokinase activators, and are able to increase insulin secretion, which makes them useful for treating type II diabetes.

This application claims benefit of Ser. No. 60/225,494 Aug. 15, 2000.

BACKGROUND OF THE INVENTION

Glucokinase (GK) is one of four hexokinases found in mammals [Colowick,S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York,N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in themetabolism of glucose, i.e., the conversion of glucose toglucose-6-phosphate. Glucokinase has a limited cellular distribution,being found principally in pancreatic β-cells and liver parenchymalcells. In addition, GK is a rate-controlling enzyme for glucosemetabolism in these two cell types that are known to play critical rolesin whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., andRuderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.),Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. Theconcentration of glucose at which GK demonstrates half-maximal activityis approximately 8 mM. The other three hexokinases are saturated withglucose at much lower concentrations (<1 mM). Therefore, the flux ofglucose through the GK pathway rises as the concentration of glucose inthe blood increases from fasting (5 mM) to postprandial (≈10-15 mM)levels following a carbohydrate-containing meal [Printz, R. G.,Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R.E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc.,Palo Alto, Calif., pages 463-496, 1993]. These findings contributed overa decade ago to the hypothesis that GK functions as a glucose sensor inβ-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer.J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenicanimals have confirmed that GK does indeed play a critical role inwhole-body glucose homeostasis. Animals that do not express GK diewithin days of birth with severe diabetes while animals overexpressingGK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. etal., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEBJ., 10, 1213-1218, 1996). An increase in glucose exposure is coupledthrough GK in β-cells to increased insulin secretion and in hepatocytesto increased glycogen deposition and perhaps decreased glucoseproduction.

The finding that type II maturity-onset diabetes of the young (MODY-2)is caused by loss of function mutations in the GK gene suggests that GKalso functions as a glucose sensor in humans (Liang, Y., Kesavan, P.,Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidencesupporting an important role for GK in the regulation of glucosemetabolism in humans was provided by the identification of patients thatexpress a mutant form of GK with increased enzymatic activity. Thesepatients exhibit a fasting hypoglycemia associated with aninappropriately elevated level of plasma insulin (Glaser, B., Kesavan,P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). Whilemutations of the GK gene are not found in the majority of patients withtype II diabetes, compounds that activate GK and, thereby, increase thesensitivity of the GK sensor system will still be useful in thetreatment of the hyperglycemia characteristic of all type II diabetes.Glucokinase activators will increase the flux of glucose metabolism inβ-cells and hepatocytes, which will be coupled to increased insulinsecretion. Such agents are useful for treating type II diabetes.

SUMMARY OF THE INVENTION

This invention provides a tetrazole selected from the group consistingof a compound of the formula:

where one of R¹ or R² is

(this tetrazole is linked to the remainder of the molecule by the N, asrepresented here) and the other is hydrogen, halogen, lower alkylsulfonyl, perfluoro-lower alkyl, cyano, or nitro; R³ is cycloalkyl; R⁴is —C(O)NHR⁶ or a five- or six-membered heteroaromatic ring connected bya ring carbon atom to the amide group shown, which heteroaromatic ringcontains from 1 to 3 heteroatoms selected from the group consisting ofoxygen, sulfur and nitrogen with a first heteroatom being nitrogenadjacent to the connecting ring carbon atom, said heteroaromatic ringbeing unsubstituted or monosubstituted with halogen at a position on aring carbon atom other than that adjacent to said connecting carbonatom; n is 0 or 1; R⁵ is lower alkyl, or perfluoro lower alkyl; R⁶ ishydrogen or lower alkyl; and pharmaceutically acceptable salts of thetetrazole.

Formula I-A depicts the isomeric bond when it is not hydrogenated.Formula I-B depicts the bond when it is hydrogenated. Accordingly the Adenotes a trans configuration across the double bond in formula I-A, andthe * represents the asymmetric carbon atom in formula I-B. Tetrazoleswhich are compounds of formula I-B are preferably in the Rconfiguration.

The compounds of formula IA or IB are glucokinase activators useful forincreasing insulin secretion in the treatment of type II diabetes.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of formula I-A or of formula I-B is a tetrazole where R⁴is a five- or six-membered heteroaromatic ring connected by a ringcarbon atom to the amide group shown, which heteroaromatic ring containsfrom 1 to 3 heteroatoms selected from the group consisting of oxygen,sulfur and nitrogen with a first heteroatom being nitrogen adjacent tothe connecting ring carbon atom, said heteroaromatic ring beingunsubstituted or monosubstituted with halogen at a position on a ringcarbon atom other than that adjacent to said connecting carbon atom.Formula I-A1 represents this embodiment as a compound of formula I-A,and Formula I-B1 represents this embodiment as a compound of formulaI-B.

Another embodiment of formula I-A or formula I-B is a tetrazole where R⁴is —C(O)—NHR⁶ where R⁶ is hydrogen or lower alkyl. Formula I-A2represents this embodiment as a compound of formula I-A. Formula I-B2represents this embodiment as a compound of iz formula I-B.

In most tetrazoles of this invention, it is preferred that R¹ be

It is also preferred that R⁵ be lower alkyl (such as methyl). It isfurther preferred that R³ be cyclopentyl, although cyclohexyl andcycloheptyl are also possible. When R⁴ is a six-membered heteroaromaticring, it is preferably substituted or unsubstituted pyridine. When R⁴ isa 5-membered heteroaromatic ring, it is preferably substituted orunsubstituted thiazole. When substituted, either ring is preferablymonosubstituted, and the preferred substituent is halogen such as bromo.R² is preferably halogen (such as fluoro or chloro) or perfluoro loweralkyl (such as trifluoromethyl) and R⁶ is preferably methyl. Thus, atetrazole of formula IA or IB may include any one or more of theseconditions in any selected combination. In addition, any one or more ofthese conditions may be applied to any tetrazole of this invention asdescribed herein. For example, in any tetrazole of this invention withsubstituted pyridine, the preferred substituent is bromo.

In particular, in tetrazoles of formula I-A1, R¹ is

R⁵ is lower alkyl, and R³ is cyclopentyl (formula I-A1a). In oneembodiment of formula I-A1a, R⁴ is a six-membered heteroaromatic ring,in particular substituted or unsubstituted pyridine. In such atetrazole, R² may be halogen. An example is:

(E)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylamide

In another embodiment of formula I-A1a, R⁴ is a 5-memberedheteroaromatic ring, in particular substituted or unsubstitutedthiazole. In such a tetrazole, R² may be halogen or perfluoro loweralkyl, or R² may be lower alkyl sulfonyl. Examples of the formertetrazoles are

(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-N-thiazol-2-yl-acrylamide

(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-but-2-enoicacid-thiazol-2-ylamide

(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide

(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide

An example of the latter tetrazole is

(E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl-]-N-thiazol-2-yl-acrylamide

In another tetrazole of formula I-A1, R¹ is

R² is halogen and R⁴ is substituted or unsubstituted thiazole. In thesetetrazoles, R⁵ is lower alkyl or perfluoro lower alkyl. R³ may becyclohexyl, as in

(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide

(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide

Or R³ may be cycloheptyl, as in

(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide

(E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylamide

This invention is also directed to tetrazoles of formula I-A2 (i.e.tetrazoles of formula I-A) where R⁴ is —C(O)—NHR⁶ where R⁶ is hydrogenor lower alkyl. In preferred such tetrazoles, R¹ is

R⁵ is lower alkyl, R³ is cyclopentyl, and R⁶ is methyl, especially whereR² is halogen. An example of such a tetrazole is

(E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl-acryloyl}3-methyl-urea

This invention is also directed to tetrazoles of formula I-B, forexample tetrazoles of formula I-B1 (where R⁴ is a five- or six-memberedheteroaromatic ring as described in detail above). In such tetrazoles,R¹ is preferably

R⁵ is lower alkyl, and R³ is cyclopentyl (formula I-B1a). In oneembodiment of formula I-B1a, R⁴ is a six-membered heteroaromatic ring,in particular substituted or unsubstituted pyridine. In such atetrazole, R² may be halogen. Examples of such tetrazoles are

N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide

N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide

Alternatively, R² may be perfluoro lower alkyl, for example inN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionamide

In another embodiment of formula I-B1a, R⁴ is a 5-memberedheteroaromatic ring, in particular substituted or unsubstitutedthiazole. In such a tetrazole, R² may be halogen or perfluoro loweralkyl, or R² may be lower alkyl sulfonyl. Examples of these tetrazolesare

3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide

2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide

3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide

In another tetrazole of formula I-B1, R¹ is

R³ is cyclohexyl and R⁴ is substituted or unsubstituted thiazole. Inthese tetrazoles, R² is halogen. R⁵ may be lower alkyl as in2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamideor perfluoro lower alkyl as in2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide.

In any tetrazoles of this invention, R² and R¹ can be exchanged so thatR² is

in particular certain tetrazoles of formula I-B1. In these tetrazoles,it is preferred that R¹ is lower alkyl sulfonyl, R⁴ is substituted orunsubstituted thiazole, and R³ is cyclopentyl. An example of such atetrazole is

3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide

This invention is also directed to tetrazoles of formula I-B2 (i.e.tetrazoles of formula I-B) where R⁴ is —C(O)—NHR⁶ where R⁶ is hydrogenor lower alkyl. In such tetrazoles, it is preferred that R¹ is

R³ is cyclopentyl, R⁶ is methyl, and R² is perfluoro lower alkyl orhalogen. Examples of such tetrazoles are

1-{3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl}-propionyl-3-methyl-urea

1-{2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionyl-3-methyl-urea

As used herein, the term “lower alkyl” means straight chain or branchedchain alkyl groups having from 1 to 4 carbon atoms, such as methyl,ethyl, propyl, isopropyl, preferably methyl and ethyl. As used herein,“cycloalkyl” means a saturated hydrocarbon ring having from 3 to 8carbon atoms, preferably from 5 to 7 carbon atoms. As used herein,“perfluoro-lower alkyl” means any lower alkyl group wherein all of thehydrogens of the lower alkyl group are substituted or replaced byfluoro, such as trifluoromethyl, pentafluoroethyl, heptafluoropropyl,etc.

As used herein, “lower alkyl sulfonyl” means a lower alkyl group asdefined above bound to the rest of the molecule through the sulfur atomin the sulfonyl group.

As used herein, the term “halogen” or “halo” unless otherwise stateddesignates all four halogens, i.e. fluorine, chlorine, bromine andiodine (fluoro, chloro, bromo, and iodo).

The heteroaromatic ring defined by R⁴ is five- or six-memberedheteroaromatic ring (e.g. an aromatic ring having at least oneheteroatom) which is connected by a ring carbon to the amide group shownin formula IA or formula 1B. This ring has from 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen, and sulfur. Thenitrogen is found adjacent to the connecting ring carbon atom. Preferredheteroaromatic rings include pyridinyl and thiazolyl. The rings may beunsubstituted, or mono-substituted with a halogen at a position on aring carbon which is not adjacent to the connecting ring carbon atom.

The term “trans” as used herein designates that the largest substituentsattached across the double bond are on opposite sides of the double bondand have the “E” configuration. The term “cis” designates that the twolargest substituents attached across the double bond are on the sameside as the double bond.

In the compounds of formula I-B, the “*” designates the asymmetriccarbon atom in the compounds with the R optical configuration beingpreferred. The compounds of formula I-B may be present in the R form oras a racemic or other mixture of compounds having the R and S opticalconfiguration at the asymmetric carbon shown. The pure R enantiomers arepreferred. As stated above, the compounds of this invention are usefulas glucokinase activators for increasing insulin secretion for treatmentof type II diabetes. Compounds of formula I-A having the transconfiguration across the double bond (represented by the Δ) have thisglucokinase activity.

The term “pharmaceutically acceptable salts” as used herein include anysalt with both inorganic or organic pharmaceutically acceptable acidssuch as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,succinic acid, tartaric acid, methanesulfonic acid, para-toluenesulfonic acid and the like. The term “pharmaceutically acceptable salts”also includes any pharmaceutically acceptable base salt such as aminesalts, trialkyl amine salts and the like. Such salts can be formed quitereadily by those skilled in the art using standard techniques.

The three Schemes that follow demonstrate how to make tetrazoles offormulae IA or IB from known starting materials.

R¹, R², R³, R⁴, R⁵, and n are as in formulae I-A and I-B. As shown inthe Schemes, the R¹ and R² positions are interchangeable. Therefore theSchemes include and demonstrate the same reactions, intermediates, andcompounds with the tetrazole or its precursors in the R² position andthe other R¹/R² variables (hydrogen, halogen, lower alkyl sulfonyl,perfluoro lower alkyl, cyano, or nitro) in the R¹ position and viceversa.

The compounds of this invention are produced by reactingphenyl-substituted tetrazoles (II, II′, IV, or IV′) withcycloalkyl-substituted acrylic acid lower alkyl esters (VII) to obtaintetrazolyl-phenyl cycloalkyl propenoic ester (VIII), which is hydrolyzedor reduced and hydrolyzed to give the corresponding propenoic or acrylicacid (IX or XIII), to which is added the desired heteroaromatic ring orurea/substituted urea to obtain a compound of formula I-A or formulaI-B. The phenyl-substituted tetrazoles (II, II′, IV, or IV′) may beproduced from the appropriate substituted anilines which are known andavailable materials or can be produced by a skilled person from knownmaterials. The cycloalkyl-substituted acrylic acid lower alkyl estersmay be produced from cycloalkyl halides, which are similarly known andavailable materials or can be produced by a skilled person from knownmaterials. These reactions are discussed in more detail below.

Scheme 1 shows how to obtain starting materials for compounds of thisinvention. For compounds where R⁵ is lower alkyl or perfluoro loweralkyl, substituted aniline I is reacted with lower alkyl or perfluorolower alkyl carboxylic acid (corresponding to R⁵) using conventionalmethods for converting an amine to an imine, for example in a suspensionof triphenylphosphine in carbon tetrachloride treated with an organicbase such as triethylamine. Accordingly the reaction proceeds by way ofan imidoyl halide (e.g. chloride) intermediate, which is reacted with anazide such as sodium azide as to obtain tetrazole II by conventionalmethods for tetrazole formation from an imidoyl chloride.

For compounds of this invention where R⁵ is lower alkyl, an alternateroute is acylation of aniline I as described above to acetamide IIIunder standard conditions (such as acetic anhydride in tetrahydrofuran),followed by reaction with an azide to obtain tetrazole IV byconventional methods for tetrazole formation from a lower alkyl amide.

Aniline I where X is either iodo or bromo and either of R¹ or R² ishydrogen, nitro, fluorine, chlorine, bromine, thiol, and trifluoromethylor where R¹ is thiomethyl or where R² is cyano, is known andcommercially available, and may also be made by a skilled chemist fromknown materials. Other aniline I compounds may be made by a skilledchemist from known materials.

For example aniline 1 where R¹ or R² is C₁-C₄ lower alkyl sulfonyl canbe made from aniline I where R¹ or R² is thiol. The thiol is alkylatedunder standard conditions to provide the lower alkyl thio, which canthen be oxidized to the corresponding lower alkyl sulfonyl. Anyconventional method of oxidizing alkyl thio substituents to sulfones canbe used to effect this conversion.

Aniline I where R¹ is cyano (and X is bromo) can be made from aniline Iwhere R¹ is nitro and X is bromo by reducing the nitro to an amine byany conventional method, then diazotizing the amine to the correspondingdiazonium salt, and reacting with a standard cyano group transferringagent to obtain aniline I where R¹ is cyano.

Aniline I where R¹ or R² are perfluoro lower alkyl can be made from thecorresponding halo compounds of formula VIII. Any conventional methodfor converting an aromatic halo group to a desired perfluoro lower alkylgroup may be used (see for example, Katayama, T.; Umeno, M., Chem. Lett.1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3, 630; Novak,J.; Salemink, C. A., Synthesis, 1983, 7, 597; Eapen, K. C.; Dua, S. S.;Tamboroski, C., J. Org. Chem. 1984, 49, 478; Chen, Q, -Y.; Duan, J. -X.J. Chem. Soc. Chem. Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.;Jone, C. W.; Landon, P.; Bisohp, D.; Blade, R. J., Tetrahedron Lett.1989, 2133; Powell, R. L.; Heaton, C. A, U.S. Pat. No. 5,113,013).

Aniline I where R¹ or R² is iodo may be made from the correspondingnitro compounds of formula VIII. The nitro is reduced to an amine andthe amine is diazotized to the diazonium salt, which is then convertedto the iodo compound by conventional methods (see for example Lucas, H.J. and Kennedy, E. R., Org. Synth. Coll. Vol. II 1943, 351).

For compounds of formula I-A, the above tetrazoles are coupled withacrylic acid lower alkyl ester (VIII) to ultimately providetetrazolyl-phenyl cycloalkyl propenoic acid IX to which may be coupled aheteroaromatic amine or a urea or lower alkyl urea to obtain a compoundof formula I-A.

Scheme 2 shows how to obtain compounds of formula I-A in more detail. R³is cycloalkyl. To obtain cycloalkyl-2-iodo-acrylic acid methyl esterVII, organozinc reagent Va (obtained by conventional methods fromcommercially available iodide V) or commercially available Grignardreagent Vb and soluble copper reagent is reacted with lower alkylpropiolate in a regio- and stereo-selective 1,4-conjugate addition toobtain a vinylcopper intermediate which upon iodonolysis under standardconditions produces VII where R³ and the iodo substituent are in synrelationship to each other. The addition operates by way of a cycloalkylcopper cyano zinc or magnesium halide intermediate obtained by treatingVa or Vb with copper cyanide and lithium chloride in an aprotic solventsuch as tetrahydrofuran. Compound VII is then reacted with activatedzinc metal (Knochel and Rao, Tetrahedron 49:29, 1993) to give avinylzinc intermediate which may be coupled with either compound II orcompound IV in the presence of a source of Pd(0) to givetetrazole-phenyl-cycloalkyl-acrylic acid methyl ester VIII with thephenyl-substituted tetrazole replacing the iodide to yield the transorientation across the double bond.

Compound VIII is then hydrolyzed under standard alkaline conditions tothe corresponding acid IX. Heterocyclic compound X may then be formed bycoupling the desired heteroaromatic amine to compound IX underconventional conditions for adding an amine to an acid. Urea compound XImay be obtained by coupling urea or lower alkyl urea to compound IXunder conventional conditions for converting an acid to a urea.

Compound VIII is the starting material for compounds of formula I-B. Asshown in Scheme 3, these compounds may be obtained by reducing compoundVIII to tetrazole-phenyl-cycloalkyl propanoic acid lower alkyl esterXII. This can be accomplished using conventional metal catalysts such asnickel in the presence of a reducing agent under standard conditions.Compound XII is then hydrolyzed under standard conditions to provide thecorresponding acid XIII. Heterocyclic compound XIV may then be formed bycoupling the desired heteroaromatic amine to compound XIII underconventional conditions for adding an amine to an acid. Urea compound XVmay be obtained by coupling urea or lower alkyl urea to compound XIIIunder conventional conditions for converting an acid to a urea.

If it is desired to produce the R enantiomer of the compound of formulaI-B free of the other enantiomers, the compound of formula XIII can beseparated into this isomer from its racemate by any conventionalchemical means. Among the preferred chemical means is to react thecompound of formula XIII with an optically active base. Any conventionaloptically active base can be utilized to carry out this resolution.Among the preferred optically active bases are the optically activeamine bases such as alpha-methylbenzylamine, quinine,dehydroabietylamine and alpha-methylnaphthylamine. Any of theconventional techniques utilized in resolving organic acids withoptically active organic amine bases can be utilized in carrying outthis reaction.

In the resolution step, the compound of formula XIII is reacted with theoptically active base in an inert organic solvent medium to producesalts of the optically active amine with both the R and S isomers of thecompound of formula XIII. In the formation of these salts, temperaturesand pressure are not critical and the salt formation can take place atroom temperature and atmospheric pressure. The R and S salts can beseparated by any conventional method such as fractional crystallization.After crystallization, each of the salts can be converted to therespective compounds of formula XIII in the R and S configuration byhydrolysis with an acid. Among the preferred acids are dilute aqueousacids, i.e., from about 0.001N to 2N aqueous acids, such as aqueoussulfuric or aqueous hydrochloric acid. By means of measuring the opticalrotation of the optically pure crystallized acid of formula XIII, onecan obtain the configuration of this crystalline material. If thiscrystallized acid has a negative rotation, then this crystallized acidhas the R configuration. The configuration of formula XIII which isproduced by this method of resolution is carried out throughout theentire reaction scheme to produce the desired R of formula IB. Theseparation of R and S isomers can also be achieved using an enzymaticester hydrolysis of any lower alkyl esters corresponding to the compoundof the formula XII (see, for example, Ahmar, M.; Girard, C.; Bloch, R.,Tetrahedron Lett, 1989, 7053), which results in the formation ofcorresponding chiral acid and chiral ester. The ester and the acid canbe separated by any conventional method of separating an acid from anester. The preferred method of resolution of racemates of the compoundsof the formula XIII is via the formation of corresponding diastereomericesters or amides. These diastereomeric esters or amides can be preparedby coupling the carboxylic acids of the formula XIII with a chiralalcohol or a chiral amine. This reaction can be carried out using anyconventional method of coupling a carboxylic acid with an alcohol or anamine. The corresponding diastereomers of compounds of the formula XIIIcan then be separated using any conventional separation methods. Theresulting pure diastereomeric esters or amides can then be hydrolyzed toyield the corresponding pure R and S isomers. The hydrolysis reactioncan be carried out using any conventional method to hydrolyze an esteror an amide without racemization.

All of the compounds of formula IA or formula IB described in theExamples activated glucokinase in vitro in accordance with the proceduredescribed in Example A.

The following compounds were tested and found to have excellentglucokinase activating activity in vivo when administered orally inaccordance with the procedure described in Example B.

N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide

N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionamide

3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide

(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide

(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide

(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide

(E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylamide

(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide

(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide

This invention will be better understood from the following examples,which are for purposes of illustration and are not intended to limit theinvention defined in the claims that follow thereafter.

EXAMPLE 1 2-[4-[(5-methyl)-1-tetrazolyl]-3-fluoro phenyl]-3-cyclopentylN-thiazol-2-yl propionamide

A solution of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred for 10 minat 0° C. and then was allowed to warm to 25° C. where it was stirred for2 h. After this time, thin layer chromatography analysis of the reactionmixture indicated the absence of starting material. The reaction mixturewas then concentrated in vacuo to afford a crude residue. The residueprecipitated from diethyl ether (50 mL) and hexanes (50 mL). The solidwas collected by filtration and washed with hexanes to affordN-(2-fluoro-4-iodo-phenyl)-acetamide (5.12 g, 92%) as a whitecrystalline solid: mp 152-154° C.; EI-HRMS m/e calcd for C₈H₇FINO (M⁺)278.9556, found 278.9559.

A suspension of N-(2-fluoro-4-iodo-phenyl)-acetamide (5 g, 18.24 mmol)in acetonitrile (100 mL) was cooled to 0° C. and then treated withsodium azide (3.56 g, 54.7 mmol). The reaction mixture was then treatedwith trifluoromethanesulfonic anhydride (13.6 g, 48 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (100 mL) and water (100 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (1×50 mL). The combined organic extracts were washed with asaturated aqueous sodium chloride solution (1×100 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate)afforded 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (3.45 g, 62%)as a white solid: mp 122-124° C.; EI-HRMS m/e calcd for C₈H₆FIN₄ (M⁺)303.9621, found 303.9615.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (prepared in Example7, 2.21 g, 7.5 mmol) in dry tetrahydrofuran (3 mL) over 3 min. Theresulting reaction mixture was then stirred at 40-45° C. for 1 h andthen stirred overnight at 25° C. The reaction mixture was then dilutedwith dry tetrahydrofuran (5 mL), and the stirring was stopped to allowthe excess zinc dust to settle down (˜2 h). In a separate reactionflask, bis(dibenzylideneacetone)palladium(0) (90 mg, 0.16 mmol) andtriphenylphosphine (160 mg, 0.6 mmol) in dry tetrahydrofuran (10 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.52 g, 5 mmol) andthe freshly prepared zinc compound in tetrahydrofuran. The resultingbrick red solution was stirred at 25° C. over the weekend and thenheated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C.and then poured into a saturated aqueous ammonium chloride solution (50mL), and the organic compound was extracted into ethyl acetate (3×50mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate)afforded(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (1.14 g, 68%) as a light yellow solid: mp 111-114° C.;EI-HRMS m/e calcd for C₁₇H₁₉FN₄O₂ (M⁺) 330.1492, found 330.1493.

A solution of nickel (II) chloride hexahydrate (115 mg, 0.24 mmol) and(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (400 mg, 1.21 mmol) in methanol (10 mL) was cooled to0° C. and then treated with sodium borohydride (275 mg, 3.63 mmol) intwo portions. After the addition, the black reaction mixture was stirredfor 15 min at 0° C. and then allowed to warm to 25° C. where it wasstirred for 15 h. The reaction mixture was concentrated in vacuo, andthe residue was diluted with a 3N aqueous hydrochloric acid solution (30mL) and ethyl acetate (50 mL). The two layers were separated. Theorganic layer was washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford racemic3-cyclopentyl-2-[3-fluoro)-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid methyl ester (400 mg, 99%) as a viscous oil: EI-HRMS m/e calcd forC₁₇H₂₁FN₄O₂ (M⁺) 332.1648, found 332.1645.

A solution of3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid methyl ester (400 mg, 1.2 mmol) in ethanol (8 mL) was treated witha 1N aqueous sodium hydroxide solution (2.5 mL). The solution was heatedat 45-50° C. for 5 h, at which time, thin layer chromatography analysisof the reaction mixture indicated the absence of starting material. Thereaction mixture was concentrated in vacuo to remove ethanol. Theresidue was diluted with water (40 mL) and extracted with diethyl ether(1×50 mL) to remove any neutral impurities. The aqueous layer was thenacidified with a 1N aqueous hydrochloric acid solution, and theresulting acid was extracted into ethyl acetate (2×50 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid (360 mg, 94%) as a yellow solid: EI-HRMS m/e calcd for C₁₆H₁₉FN₄O₂(M⁺) 318.1487, found 318.1492.

A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylenechloride (6 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid (175 mg, 0.55 mmol). The clear solution was stirred for 15 min at0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h.The reaction mixture was then treated with 2-aminothiazole (275 mg, 2.75mmol), and the resulting suspension was stirred for 2 d at 25° C. Thereaction mixture was then concentrated in vacuo to remove methylenechloride, and the residue was diluted with ethyl acetate (50 mL) and a1N aqueous hydrochloric acid solution (25 mL). The two layers wereseparated, and the aqueous layer was extracted with ethyl acetate (1×25mL). The combined organic extracts were successively washed with a 1Naqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodiumbicarbonate solution (1×50 mL) and a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica,2/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide(80 mg, 36%) as an amorphous white solid: EI-HRMS m/e calcd forC₁₉H₂₁FN₆OS (M⁺) 400.1482, found 400.1476.

EXAMPLE 2N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide

A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylenechloride (6 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid (prepared in Example 1, 175 mg, 0.55 mmol). The clear solution wasstirred for 15 min at 0° C. and then allowed to warm to 25° C. where itwas stirred for 1.5 h. The reaction mixture was then treated with2-amino-5-bromopyridine (476 mg, 2.75 mmol), and the resultingsuspension was stirred for 2 d at 25° C. The reaction mixture was thenconcentrated in vacuo to remove methylene chloride, and the residue wasdiluted with ethyl acetate (50 mL) and water (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×25 mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FTASH 40S, Silica, 2/1 hexanes/ethyl acetate) affordedN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide(190 mg, 73%) as a white solid: mp 73-78° C.; EI-HRMS m/e calcd forC₂₁H₂₂BrFN₆O (M⁺) 472.1022, found 472.1022.

EXAMPLE 32-[3-Chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (prepared in Example7, 1.26 g, 4.5 mmol) in dry tetrahydrofuran (2 mL) over 3 min. Thereaction mixture was then stirred at 40-45° C. for 1 h and then stirredovernight at 25° C. The reaction mixture was then diluted with drytetrahydrofuran (3 mL), and the stirring was stopped to allow the excesszinc dust to settle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) andtriphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (4 mL wasstirred at 25° C. under argon for 10 min and then treated with1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (prepared in Example 4,875 mg, 2.73 mmol) and the freshly prepared zinc compound intetrahydrofuran. The resulting brick red solution was stirred at 25° C.over the weekend and then heated at 40-45° C. for 4 h. The reactionmixture was cooled to 25° C. and then poured into a saturated aqueousammonium chloride solution (50 mL), and the organic compound wasextracted into ethyl acetate (3×35 mL). The combined organic extractswere washed with a saturated aqueous sodium chloride solution (1×100mL), dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1to 1/1 hexanes/ethyl acetate) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylicacid methyl ester (859 mg, 91%) as a light yellow semi-solid: EI-HRMSm/e calcd for C₁₇H₁₉ClN₄O₂ (M⁺) 346.1196, found 346.1190.

A solution of nickel (II) chloride hexahydrate (180 mg, 0.8 mmol) and(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylicacid methyl ester (695 mg, 2.0 mmol) in methanol (15 mL) was cooled to0° C. and then treated with sodium borohydride (454 mg, 12 mmol) in fiveportions. After the addition, the black reaction mixture was stirred for15 min at 0° C. and then allowed to warm to 25° C. where it was stirredfor 2 d. The reaction mixture was concentrated in vacuo, and the residuewas diluted with a 3N aqueous hydrochloric acid solution (50 mL) andethyl acetate (75 mL). The two layers were separated. The organic layerwas washed with a saturated aqueous sodium chloride solution (1×50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo to afford racemic2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd forC₁₇H₂₁ClN₄O₂ (M⁺) 348.1353, found 348.1359.

A solution of2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid methyl ester ester (690 mg, 2.0 mmol) in ethanol (20 mL) wastreated with a 1N aqueous sodium hydroxide solution (4 mL). The solutionwas heated at 45-50° C. for 3 h, at which time, thin layerchromatography analysis of the reaction mixture indicated the absence ofstarting material. The reaction mixture was concentrated in vacuo toremove ethanol. The residue was diluted with water (50 mL) and extractedwith diethyl ether (1×60 mL) to remove any neutral impurities. Theaqueous layer was then acidified with a 1N aqueous hydrochloric acidsolution, and the resulting acid was extracted into ethyl acetate (2×50mL). The combined organic layers were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to afford2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid (604 mg, 90%) as an amorphous white solid: EI-HRMS m/e calcd forC₁₆H₁₉ClN₄O₂ (M⁺) 334.1196, found 334.1193.

A solution of triphenylphosphine (236 mg, 0.9 mmol) in methylenechloride (6 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (160 mg, 0.9 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with the2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid (151 mg, 0.45 mmol). The clear solution was stirred for 15 min at0° C. and then allowed to warm to 25° C. where it was stirred for 2 h.The reaction mixture was then treated with 2-aminothiazole (135 mg, 1.35mmol), and the resulting suspension was stirred for 20 h at 25° C. Thereaction mixture was then concentrated in vacuo to remove methylenechloride, and the residue was diluted with ethyl acetate (30 mL) and a1N aqueous hydrochloric acid solution (30 mL). The two layers wereseparated, and the aqueous layer was extracted with ethyl acetate (1×20mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide(80 mg, 42%) as a white solid: mp 190-193° C.; EI-HRMS m/e calcd forC₁₉H₂₁ClN₆OS (M⁺) 416.1186, found 416.1183.

EXAMPLE 42-[3-Chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide

A mixture of zinc dust (16.34 g, 250 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (6 mL) under argon was treated with 1,2-dibromoethane(0.94 g, 5 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (0.54 g, 5mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of cyclohexyl iodide(21 g, 100 mmol) in dry tetrahydrofuran (30 mL) over 15 min. During theaddition, the temperature rose to 60° C. The reaction mixture was thenstirred for 3 h at 40-45° C. The reaction mixture was then cooled to 25°C. and diluted with dry tetrahydrofuran (60 mL). The stirring wasstopped to allow the excess zinc dust to settle down (3 h). In aseparate reaction flask, a mixture of lithium chloride (8.48 g, 200mmol, predried at 130° C. under high vacuum for 3 h) and copper cyanide(8.95 g, 100 minol) in dry tetrahydrofuran (110 mL) was stirred for 10min at 25° C. to obtain a clear solution. The reaction mixture wascooled to −70° C. and then slowly treated with the freshly prepared zincsolution using a syringe. After the addition, the reaction mixture wasallowed to warm to 0° C. where it was stirred for 5 min. The reactionmixture was again cooled back to −70° C. and then slowly treated withmethyl propiolate (7.56 g, 90 mmol). The resulting reaction mixture wasstirred for 15 h at −70° C. to −50° C. and then slowly treated with asolution of iodine (34.26 g, 135 mmol) in dry tetrahydrofuran (30 mL),with the temperature kept at −70° C. to −60° C. After addition of theiodine solution, the cooling bath was removed, and the reaction mixturewas allowed to warm to 25° C. where it was stirred for 2 h. The reactionmixture was then poured into a solution consisting of a saturatedaqueous ammonium chloride solution (400 mL) and ammonium hydroxide (100mL), and the organic compound was extracted into ethyl acetate (3×250mL). The combined organic extracts were successively washed with asaturated aqueous sodium thiosulfate solution (1×500 mL) and a saturatedaqueous sodium chloride solution (1×500 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/diethylether) afforded (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (26.3g, 99%) as a light pink oil: EI-HRMS m/e calcd for C₁₀H₁₅IO₂ (M⁺)294.0117, found 294.0114.

A suspension of triphenylphospine (11.7 g, 44.8 mmol) in carbontetrachloride (8 mL, 83 mmol) was cooled to 0° C. and then treated withtriethylamine (2.5 mL, 18 mmol) and acetic acid (1.15 mL, 20 mmol). Thereaction mixture was stirred at 0° C. for 10 min and then treated with asolution of 2-chloro-4-iodoaniline (5.07 g, 20 mmol) in carbontetrachloride (12 mL, heated to obtain a solution). The resulting lightbrown suspension was allowed to warm to 25° C. and then it was refluxedovernight. The reaction mixture was cooled to 25° C. and thenconcentrated in vacuo. The resulting solid residue was then diluted withhexanes (50 mL) and methylene chloride (50 mL). The precipitated solidwas collected by filtration and washed with hexanes. The filtrate wasconcentrated in vacuo, and the resulting residue was diluted withdiethyl ether (100 mL). The precipitated solid was collected byfiltration and washed with hexanes, and the filtrate was concentrated invacuo. The resulting residue was again diluted with hexanes (100 mL),and the precipitated solid was collected by filtration. The filtrate wasfinally concentrated in vacuo to afford the imidoyl chlorideintermediate (4.08 g) as a liquid. This crude imidoyl chlorideintermediate (4.08 g, 13 mmol) was treated with sodium azide (1.04 g, 16mmol) and acetic acid (10 mL). The reaction was exothermic, and theresulting reaction mixture was stirred for 1 h at 25° C. The reactionmixture was then heated at 70° C. for 2 h, at which time, thin layerchromatography analysis of the reaction mixture indicated the absence ofthe imidoyl chloride intermediate. The cloudy yellow suspension wascooled to 25° C. and then diluted with water (100 mL) and extracted withethyl acetate (2×75 mL). The combined organic extracts were washedsuccessively with a saturated aqueous sodium bicarbonate solution (1×100mL) and a saturated aqueous sodium chloride solution (1×100 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40M, Silica, 6/1 hexanes/diethyl ether)afforded 1-(2-chloro-4-iodo-plenyl)-5-methyl-1H-tetrazole (350 mg, 6%)as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd for C₈H₆ClIN₄ (M⁺)319.9327, found 319.9325.

A mixture of zinc dust (320 mg, 5 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(94 mg, 0.5 mmol). The zinc suspension was then heated with a heat gunto ebullition, allowed to cool, and heated again. This process wasrepeated three times to make sure the zinc dust was activated. Theactivated zinc dust suspension was then treated with trimethylsilylchloride (55 mg, 0.5 mmol), and the suspension was stirred for 15 min at25° C. The reaction mixture was then treated dropwise with a solution of(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (588 mg, 2 mmol) indry tetrahydrofuran (2 mL). After the addition, the reaction mixture wasstirred for 1 h at 40-45° C. and then stirred overnight at 25° C. Thereaction mixture was then diluted with dry tetrahydrofuran (2 mL), andthe stirring was stopped to allow the excess zinc dust to settle down(˜2 h). In a separate reaction flask,bis(dibenzylideneacetone)-palladium(0) (27 mg, 0.05 mmol) andtriphenylphosphine (57 mg, 0.2 mmol) in dry tetrahydrofuran (4 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (320.5 mg, 1 mmol) andthe freshly prepared zinc compound in tetrahydrofuran. The resultingbrick red solution was heated at 50° C. for 15 h. The reaction mixturewas cooled to 25° C. and then poured into a saturated aqueous ammoniumchloride solution (30 mL), and the organic compound was extracted intoethyl acetate (3×20 mL). The combined organic extracts were washed witha saturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 4/1/1 hexanes/ethylacetate/methylene chloride) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (233 mg, 64%) as an amorphous white solid: EI-HRMS m/ecalcd for C₁₈H₂₁ClN₄O₂ (M⁺) 360.1353, found 360.1354.

A solution of nickel (II) chloride hexahydrate (78 mg, 0.328 mmol) and(E)-2-[3-chloro4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (295 mg, 0.82 mmol) in methanol (8 mL) was cooled to0° C. and lien treated with sodium borohydride (186 mg, 4.92 mmol) infour portions. After the addition, the black reaction mixture wasstirred for 15 min at 0° C. and then allowed to warm to 25° C. where itwas stirred for 24 h. The reaction mixture was then concentrated invacuo, and the residue was diluted with water (30 mL) and ethyl acetate(50 mL). The two layers were separated. The organic layer was washedsuccessively with a 3N aqueous hydrochloric acid solution (1×50 mL), asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to afford racemic2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid methyl ester (285 mg, 96%) as a viscous oil: EI-HRMS m/e calcd forC₁₈H₂₃ClN₄O₂ (M⁺) 362.1509, found 362.1516.

A solution of2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid methyl ester (278 mg, 0.76 mmol) in ethanol (6 mL) was treated witha 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heatedat 45-50° C. for 5 h, at which time, thin layer chromatography analysisof the mixture indicated the absence of starting material. The reactionmixture was then concentrated in vacuo to remove ethanol, and theresidue was diluted with water (20 mL) and extracted with diethyl ether(1×40 mL) to remove any neutral impurities. The aqueous layer wasacidified with a 1N aqueous hydrochloric acid solution. The resultingacid was extracted into ethyl acetate (2×50 mL). The combined organiclayers were washed with a saturated aqueous sodium chloride solution(1×50 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid (226 mg, 85%) as an amorphous solid: EI-HRMS m/e calcd forC₁₇H₂₁ClN₄O₂ (M⁺) 348.1353, found 348.1354.

A solution of triphenylphosphine (281 mg, 1.07 numol) in methylenechloride (5 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (190.4 mg, 1.07 mmol). The reaction mixture wasstirred at 0° C. for 30 min and then treated with a solution of2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid (220 mg, 0.63 mmol) in methylene chloride (4 mL). The clearsolution was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 2 h. The reaction mixture was then treatedwith 2-aminothiazole (189 mg, 1.89 mmol), and the resulting suspensionwas stirred for 15 h at 25° C. The reaction mixture was concentrated invacuo to remove methylene chloride, and the residue was diluted withethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50mL). The two layers were separated, and the aqueous layer was extractedwith ethyl acetate (1×30 mL). The combined organic extracts weresuccessively washed with a saturated aqueous sodium bicarbonate solution(1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethylacetate) afforded2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide(79 mg, 29%) as an amorphous solid: EI-HRMS m/e calcd for C₂₀H₂₃ClN₆OS(M⁺) 430.1343, found 430.1343.

EXAMPLE 5N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide

A solution of triphenylphosphine (236 mg, 0.9 mmol) in methylenechloride (6 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (160 mg, 0.9 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with the2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid (prepared in Example 3, 151 mg, 0.45 mmol). The clear solution wasstirred for 15 min at 0° C. and then allowed to warm to 25° C. where itwas stirred for 2 h. The reaction mixture was then treated with2-amino-5-bromopyridine (234 mg, 1.35 mmol), and the resultingsuspension was stirred for 2 d at 25° C. The reaction mixture was thenconcentrated in vacuo to remove methylene chloride, and the residue wasdiluted with ethyl acetate (30 mL) and water (30 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×20 mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) affordedN-(5-bromo-pyridin-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionamide(90 mg, 42%) as an amorphous white solid: EI-HRMS m/e calcd forC₂₁H₂₂BrClN₆O (M⁺) 489.0727, found 489.0727.

EXAMPLE 62-[3-Chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide

A suspension of triphenylphospine (13.11 g, 50 mmol) in carbontetrachloride (8 mL, 83 mmol) was cooled to 0° C. and then treated withtriethylamine (2.78 mL, 20 mmol) and trifluoroacetic acid (1.3 mL, 16.6mmol). The reaction mixture was stirred at 0° C. for 10 min and thentreated with a solution of 2-chloro-4-iodoaniline (5.07 g, 20 mmol) incarbon tetrachloride (10 mL). The resulting light brown suspension wasallowed to warm to 25° C. and then it was refluxed overnight. Thereaction mixture was cooled to 25° C. and then concentrated in vacuo.The resulting solid residue was then diluted with hexanes (50 mL) andmethylene chloride (50 mL). The precipitated solid was collected byfiltration and washed with hexanes. The filtrate was concentrated invacuo, and the resulting residue was diluted with diethyl ether (100mL). The precipitated solid was collected by filtration and washed withhexanes, and the filtrate was concentrated in vacuo. The resultingresidue was again diluted with hexanes (100 mL), and the precipitatedsolid was collected by filtration. The filtrate was finally concentratedin vacuo to afford the imidoyl chloride intermediate (5.88 g) as a brownliquid. This crude imidoyl chloride intermediate (5.88 g, ˜16 mmol) wastreated with sodium azide (1.04 g, 16 mmol) and acetic acid (10 mL). Theresulting reaction mixture was then heated at 70° C. for 2 h, at whichtime, thin layer chromatography analysis of the reaction mixtureindicated the absence of the imidoyl chloride intermediate. The cloudyyellow suspension was cooled to 25° C. and then diluted with water (100mL) and extracted with ethyl acetate (2×75 mL). The combined organicextracts were washed successively with a saturated aqueous sodiumbicarbonate solution (1×100 mL) and a saturated aqueous sodium chloridesolution (1×100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica,8/1 hexanes/diethyl ether) afforded1-(2-chloro-4-iodo-phenyl)-5-trifluoromethyl-1H-tetrazole (5.2 g, 69%)as a light yellow solid: mp 71-73° C.; EI-HRMS m/e calcd for C₈H₃ClF₃IN₄(M⁺) 373.9043, found 373.9044.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (2 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (110 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (prepared in Example4, 1.32 g, 4.5 mmol) in dry tetrahydrofuran (2 mL) over 5 min. After theaddition, the reaction mixture was stirred for 1 h at 40-45° C. and thenstirred overnight at 25° C. The reaction mixture was then diluted withdry tetrahydrofuran (4 mL), and the stirring was stopped to allow theexcess zinc dust to settle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) andtriphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (8 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-chloro-4-iodo-phenyl)-5-trifluoromethyl-1H-tetrazole (1.12 g, 3mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was heated at 50° C. for 15 h. The reactionmixture was cooled to 25° C. and then poured into a saturated aqueousammonium chloride solution (70 mL), and the organic compound wasextracted into ethyl acetate (3×50 mL). The combined organic extractswere washed with a saturated aqueous sodium chloride solution (1×100mL), dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 hexanes/ethylacetate) afforded(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (908 mg, 73%) as an amorphous white solid: EI-HRMS m/ecalcd for C₁₈H₁₈ClF₃N₄O₂ (M⁺) 414.1070, found 414.1075.

A solution of nickel (II) chloride hexahydrate (77 mg, 0.324 mmol) and(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (674 mg, 1.62 mmol) in methanol (15 mL) was cooled to0° C. and then treated with sodium borohydride (184 mg, 4.86 mmol) infour portions. After the addition, the black reaction mixture wasstirred for 15 min at 0° C. and then allowed to warm to 25° C. where itwas stirred for 20 h. The reaction mixture was then concentrated invacuo, and the residue was diluted with water (50 mL) and ethyl acetate(100 mL). The two layers were separated. The organic layer was washedsuccessively with a 3N aqueous hydrochloric acid solution (1×50 mL), asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to afford racemic2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid methyl ester (640 mg, 95%) as a viscous oil: EI-HRMS m/e calcd forC₁₈H₂₀ClF₃N₄O₂ (M⁺) 416.1527, found 416.1529.

A solution of2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid methyl ester (634 mg, 1.52 rumol) in ethanol (10 mL) was treatedwith a 1N aqueous sodium hydroxide solution (3 mL). The solution washeated at 45-50° C. for 5 h, at which time, thin layer chromatographyanalysis of the mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo to remove ethanol, andthe residue was diluted with water (50 mL) and extracted with diethylether (1×60 mL) to remove any neutral impurities. The aqueous layer wasacidified with a 1N aqueous hydrochloric acid solution. The resultingacid was extracted into ethyl acetate (2×50 mL). The combined organiclayers were washed with a saturated aqueous sodium chloride solution(1×100 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid (375 mg, 61%) as a viscous oil: EI-HRMS m/e calcd forC₁₇H₁₈ClF₃N₄O₂ (M⁺) 402.1070, found 402.1067.

A solution of triphenylphosphine (409 mg, 1.56 mmol) in methylenechloride (8 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (277 mg, 1.56 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionicacid (370 mg, 0.92 mmol) in methylene chloride (5 mL). The clearsolution was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 2 h. The reaction mixture was then treatedwith 2-aminothiazole (276 mg, 2.76 mmol), and the resulting suspensionwas stirred for 15 h at 25° C. The reaction mixture was concentrated invacuo to remove methylene chloride, and the residue was diluted withethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (50mL). The two layers were separated, and the aqueous layer was extractedwith ethyl acetate (1×50 mL). The combined organic extracts weresuccessively washed with a saturated aqueous sodium bicarbonate solution(1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40S, Silica, 3/2 hexanes/ethylacetate) afforded2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide(83 mg, 18%) as an amorphous solid: EI-HRMS m/e calcd for C₂₀H₂₀ClF₃N₆OS(M⁺) 484.1060, found 484.1068.

EXAMPLE 73-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide

A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0° C.for 10 min and then allowed to warm to 25° C. The reaction mixture wasstirred at 25° C. for 2 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was then concentrated in vacuo. The cruderesidue precipitated from diethyl ether (50 mL) and hexanes (50 mL). Thesolid was collected by filtration and washed with hexanes to affordN-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as anamorphous white solid: EI-HRMS m/e calcd for C₉H₇BrF₃NO (M⁺) 281.8352,found 281.8348.

A suspension of N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (2.41 g,8.54 mmol) in acetonitrile (40 mL) was treated with methylene chloride(5 mL) to obtain a clear solution at 25° C. The resulting solution wastreated with sodium azide (1.24 g, 19.1 mmol), and the reaction mixturewas then cooled to 0° C. The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (3.59 g, 12.7 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (50 mL) and water (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×30 mL). The combined organic extracts were washed with a saturatedaqueous sodium chloride solution (1×100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.85 g, 70%)as a white solid: EI-HRMS m/e calcd for C₉H₆BrF₃N₄ (M⁺) 305.9728, found305.9733.

A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (710 mg, 11 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (1.54 g, 5.5 mmol) indry tetrahydrofuran (2 mL) over 3 min. The reaction mixture was thenstirred at 40-45° C. for 1 h and then stirred overnight at 25° C. Thereaction mixture was then diluted with dry tetrahydrofuran (4 mL), andthe stirring was stopped to allow the excess zinc dust to settle down (2h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)(81 mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in drytetrahydrofuran (6 mL) was stirred at 25° C. under argon for 10 min andthen treated with1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.05 g, 3.5mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was heated at 40-45° C. over the weekend.The reaction mixture was cooled to 25° C. and then poured into asaturated aqueous ammonium chloride solution (50 mL), and the organiccompound was extracted into ethyl acetate (3×35 mL). The combinedorganic extracts were washed with a saturated aqueous sodium chloridesolution (1×100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid methyl ester (1.03 g, 77.6%) as a light yellow solid: EI-HRMS m/ecalcd for C₁₈H₁₉F₃N₄O₂ (M⁺) 380.1460, found 380.1453.

A solution of nickel (II) chloride hexahydrate (102 mg, 0.428 mmol) and(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid methyl ester (814 mg, 2.14 mmol) in methanol (20 mL) was cooled to0° C. and then treated with sodium borohydride (265 mg, 7 mmol) in fiveportions. After the addition, the black reaction mixture was stirred for15 min at 0° C. and then allowed to warm to 25° C. where it was stirredfor 15 h. The reaction mixture was concentrated in vacuo, and theresidue was diluted with a 3N aqueous hydrochloric acid solution (50 mL)and ethyl acetate (75 mL). The two layers were separated. The organiclayer was washed with a saturated aqueous sodium chloride solution (1×50mL), dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo to afford racemic3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd forC₁₈H₂₁F₃N₄O₂ (M⁺) 382.1617, found 382.1617.

A solution of3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid methyl ester (870 mg, 2.27 mmol) in ethanol (12 mL) was treatedwith a 1N aqueous sodium hydroxide solution (8 mL). The solution washeated at 45-50° C. for 3 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was concentrated in vacuo to removeethanol. The residue was diluted with water (50 mL) and extracted withdiethyl ether (1×60 mL) to remove any neutral impurities. The aqueouslayer was then acidified with a 1N aqueous hydrochloric acid solution,and the resulting acid was extracted into ethyl acetate (2×50 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to afford3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid (781 mg, 93%) as a white solid: EI-HRMS m/e calcd for C₁₇H₁₉F₃N₄O₂(M⁺) 368.1460, found 368.1460.

A solution of triphenylphosphine (213 mg, 0.84 mmol) in methylenechloride (12 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (144 mg, 0.84 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with the3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid (150 mg, 0.4 mmol). The clear solution was stirred for 15 min at 0°C. and then allowed to warm to 25° C. where it was stirred for 2 h. Thereaction mixture was then treated with 2-aminothiazole (122 mg, 1.22mmol), and the resulting suspension was stirred for 15 h at 25° C. Thereaction mixture was then concentrated in vacuo to remove methylenechloride, and the residue was diluted with ethyl acetate (30 mL) and a1N aqueous hydrochloric acid solution (30 mL). The two layers wereseparated, and the aqueous layer was extracted with ethyl acetate (1×20mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 1/2 hexanes/ethyl acetate) afforded3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide(128 mg, 70%) as an amorphous solid: EI-HRMS m/e calcd for C₂₀H₂₁F₃N₆OS(M⁺) 450.1449, found 450.1454.

EXAMPLE 8N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionamide

A solution of triphenylphosphine (213 mg, 0.84 mmol) in methylenechloride (12 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (144 mg, 0.84 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with the3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid (prepared in Example 7, 150 mg, 0.4 mmol). The clear solution wasstirred for 15 min at 0° C. and then allowed to warm to 25° C. where itwas stirred for 2 h. The reaction mixture was then treated with2-amino-5-bromopyridine (122 mg, 1.22 mmol), and the resultingsuspension was stirred for 15 h at 25° C. The reaction mixture was thenconcentrated in vacuo to remove methylene chloride, and the residue wasdiluted with ethyl acetate (30 mL) and water (30 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×20 mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) affordedN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionamide(90 mg, 42%) as an amorphous white solid: EI-HRMS m/e calcd forC₂₂H₂₂BrF₃N₆O (M⁺) 522.0991, found 522.0989.

EXAMPLE 93-Cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazo1-2-yl-propionamide

A solution of isoamyl nitrite (10.05 mL, 75 mmol) in dimethyl disulfide(49.5 mL, 550 mmol) at 25° C. was slowly treated with4-bromo-2-nitroaniline (10.85 g, 50 mmol). The reaction was exothermicwith gas evolution. The resulting brown reaction mixture was heated to80-90° C. for 2 h, at which time, thin layer chromatography analysis ofthe reaction mixture indicated the absence of starting material. Thereaction mixture was cooled to 25° C. and then concentrated in vacuo.The resulting residue was dissolved in ethyl acetate (300 mL). Theorganic layer was washed successively with a 1N aqueous hydrochloricacid solution (1×300 mL) and a saturated aqueous sodium chloridesolution (1×300 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica,6/1 to 5/1 hexanes/ethyl acetate) afforded4-bromo-1-methylsulfanyl-2-nitro-benzene (12.05 g, 97%) as a brownsolid: EI-HRMS m/e calcd for C₇H₆BrNO₂S (M⁺) 246.9372, found 246.9368.

A solution of 4-bromo-1-methylsulfanyl-2-nitro-benzene (12.05 g, 48.6mmol) in methylene chloride (300 mL) was cooled to −10° C. and thentreated with 3-chloroperoxybenzoic acid (86% grade, 25.2 g, 145.8 mmol).The reaction mixture was stirred at −10° C. for 10 min and then allowedto warm to 25° C. where it was stirred for 2 h. At this time, thin layerchromatography analysis of the reaction mixture indicated the absence ofstarting material. The reaction mixture was then concentrated in vacuo.The resulting residue was dissolved in ethyl acetate (300 mL). Theorganic layer was washed successively with a saturated aqueous sodiumbicarbonate solution (4×200 mL) and a saturated aqueous sodium chloridesolution (1×300 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford a yellow solid. Recrystallizationfrom hot ethanol (50 mL) and acetonitrile (10 mL) followed by dilutionwith hexanes (300 mL) to obtain a precipitate. The solid was collectedby filtration and washed with hexanes (100 mL) to afford4-bromo-1-methanesulfonyl-2-nitro-benzene (8.68 g, 62%) as a whitesolid: mp 175.5-177° C.; EI-HRMS m/e calcd for C₇H₆BrNO₄S (M⁺) 278.9201,found 278.9210.

A light brown suspension of 4-bromo-1-methanesulfonyl-2-nitro-benzene(8.65 g, 30.9 mmol) in methanol (300 mL, not completely dissolved inmethanol even at hot condition) was treated sequentially with ammoniumchloride (24.8 g, 463.5 mmol), zinc dust (20.2 g, 309 mmol), and water(100 mL). Initially, the reaction was exothermic, and the brown colordisappeared. The reaction mixture was stirred for 1 h at 25° C. Thereaction mixture was then filtered, and the residue was washed withmethanol (50 mL) and ethyl acetate (100 mL). The filtrate wasconcentrated in vacuo, and the organic compound was extracted into ethylacetate (3×100 mL). The combined organic extracts were washed with asaturated aqueous sodium chloride solution (1×200 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 8/1 to 6/1 to 4/1 hexanes/ethylacetate) afforded 5-bromo-2-methanesulfonyl-phenylamine (5.7 g, 74%)as-a white solid: mp 107-109° C.; EI-HRMS m/e calcd for C₇H₈BrNO₂S (M⁺)248.9459, found 248.9451.

A solution of 5-bromo-2-methanesulfonyl-phenylamine (5.7 g, 19.5 mmol)in dry tetrahydrofuran (30 mL) at 25° C. was treated with acetylchloride (6.28 g, 80 mmol). The resulting solution was stirred overnightat 25° C., at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then diluted with water (100 mL) and ethyl acetate(100 mL). The two layers were separated, and the aqueous layer wasextracted with ethyl acetate (1×100 mL). The combined organic extractswere washed with a saturated aqueous sodium chloride solution (1×200mL), dried over anhydrous sodium sulfate, filtered, and concentrated invacuo to afford a brown solid. The brown solid was treated with diethylether (50 mL) and hexanes (50 mL). The white solid was collected byfiltration and washed with hexanes (50 mL) to affordN-(5-bromo-2-methanesulfonyl-phenyl)-acetamide (4.55 g, 80%) as a whitesolid: mp 157-160° C.; EI-HRMS m/e calcd for C₉H₁₀BrNO₃S (M⁺) 290.9565,found 290.9560.

A solution of N-(5-bromo-2-methanesulfonyl-phenyl)-acetamide (350 mg,1.2 mmol) in acetonitrile (6 mL) at 25° C. was treated with sodium azide(78 mg, 1.2 mmol). The reaction mixture was cooled to 0° C. and thentreated with trifluoromethanesulfonic anhydride (0.24 mL, 1.2 mmol). Theresulting reaction mixture was allowed to warm to 25° C. where it wasstirred overnight, at which time, thin layer chromatography analysis ofthe reaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (50 mL) and water (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×30 mL). The combined organic extracts were washed with a saturatedaqueous sodium chloride solution (1×100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded1-(5-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (254 mg, 67%)as a white solid: mp 174-184° C.; EI-HRMS m/e calcd for C₉H₉BrN₄O₂S (M⁺)315.9630, found 315.9634.

A mixture of zinc dust (330 mg, 5 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(93 mg, 0.5 mmol). The zinc suspension was then heated with a heat gunto ebullition, allowed to cool, and heated again. This process wasrepeated three times to make sure the zinc dust was activated. Theactivated zinc dust suspension was then treated with trimethylsilylchloride (54 mg, 0.5 mmol), and the suspension was stirred for 15 min at25° C. The reaction mixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (prepared in Example7, 420 mg, 1.5 mmol) in dry tetrahydrofuran (1 mL). The resultingreaction mixture was then stirred at 40-45° C. for 1 h and then stirredovernight at 25° C. The reaction mixture was then diluted with drytetrahydrofuran (3 mL), and the stirring was stopped to allow the excesszinc dust to settle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (27 mg, 0.05 mmol) andtriphenylphosphine (52 mg, 0.2 mmol) in dry tetrahydrofuran (3 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(5-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (237 mg, 0.75mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was heated at 40-45° C. over the weekend.The reaction mixture was cooled to 25° C. and then poured into asaturated aqueous ammonium chloride solution (30 mL), and the organiccompound was extracted into ethyl acetate (3×30 mL). The combinedorganic extracts were washed with a saturated aqueous sodium chloridesolution (1×100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica,3/1 to 1/1 hexanes/ethyl acetate) afforded(E)-3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (266 mg, 91%) as a white solid: mp 164-166° C.;EI-HRMS m/e calcd for C₁₈H₂₂N₄O₄S (M⁺) 390.1362, found 390.1368.

A solution of nickel (II) chloride hexahydrate (12.2 mg, 0.05 mmol) and(E)-3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (100 mg, 0.26 mmol) in methanol (5 mL) was cooled to0° C. and then treated with sodium borohydride (29 mg, 0.77 mmol). Afterthe addition, the black reaction mixture was stirred for 15 min at 0° C.and then allowed to warm to 25° C. where it was stirred for 15 h. Thereaction mixture was concentrated in vacuo, and the residue was dilutedwith a 3N aqueous hydrochloric acid solution (10 mL) and ethyl acetate(25 mL). The two layers were separated. The organic layer was washedwith a saturated aqueous sodium chloride solution (1×25 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford racemic3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid methyl ester (105 mg, 99%) as a viscous oil: EI-HRMS m/e calcd forC₁₈H₂₄N₄O₄S (M⁺) 392.1518, found 392.1526.

A solution of3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid methyl ester (102 mg, 0.26 numol) in ethanol (3 mL) was treatedwith a 1N aqueous sodium hydroxide solution (0.6 mL). The solution washeated at 45-50° C. for 5 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was concentrated in vacuo to removeethanol. The residue was diluted with water (20 mL) and extracted withdiethyl ether (1×30 mL) to remove any neutral impurities. The aqueouslayer was then acidified with a 1N aqueous hydrochloric acid solution,and the resulting acid was extracted into ethyl acetate (2×25 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×50 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to afford3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid (88 mg, 89%) as an amorphous white solid: EI-HRMS m/e calcd forC₁₇H₂₂N₄O₄S (M⁺) 378.1362, found 378.1364.

A solution of triphenylphosphine (100 mg, 0.38 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (68 mg, 0.38 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionicacid (85 mg, 0.22 mmol) in methylene chloride (3 mL). The clear solutionwas stirred for 15 min at 0° C. and then allowed to warm to 25° C. whereit was stirred for 1.5 h. The reaction mixture was then treated with2-aminothiazole (55 mg, 0.55 mmol), and the resulting suspension wasstirred for 2 d at 25° C. The reaction mixture was then concentrated invacuo to remove methylene chloride, and the residue was diluted withethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (25mL). The two layers were separated, and the aqueous layer was extractedwith ethyl acetate (1×25 mL). The combined organic extracts weresuccessively washed with a 1N aqueous hydrochloric acid solution (1×50mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and asaturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 2/1 to 1/1 hexanes/ethylacetate) afforded3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide(42 mg, 41%) as a white solid: mp 148-154° C.; EI-HRMS m/e calcd forC₂₀H₂₄N₆O₃S₂ (M⁺) 460.1351, found 460.1356.

EXAMPLE 101-{3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-urea

A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0° C.for 10 min and then allowed to warm to 25° C. The reaction mixture wasstirred at 25° C. for 2 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was then concentrated in vacuo. The cruderesidue precipitated from diethyl ether (50 mL) and hexanes (50 mL). Thesolid was collected by filtrated and washed with hexanes to affordN-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as anamorphous white solid: EI-HRMS m/e calcd for C₉H₇BrF₃NO (M⁺) 281.8352,found 281.8348.

A suspension of N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (2.41 g,8.54 mmol) in acetonitrile (40 mL) was treated with methylene chloride(5 mL) to obtain a clear solution at 25° C. The resulting solution wastreated with sodium azide (1.24 g, 19.1 mmol), and the reaction mixturewas then cooled to 0° C. The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (3.59 g, 12.7 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (50 mL) and water (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×30 mL). The combined organic extracts were washed with a saturatedaqueous sodium chloride solution (1×100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.85 g, 70%)as a white solid: EI-HRMS m/e calcd for C₉H₆BrF₃N₄ (M⁺) 305.9728, found305.9733.

A mixture of lithium chloride (8.48 g, 209 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (710 mg, 11 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (1.54 g, 5.5 mmol) indry tetrahydrofuran (2 mL) over 3 min. The reaction mixture was thenstirred at 40-45° C. for 1 h and then stirred overnight at 25° C. Thereaction mixture was then diluted with dry tetrahydrofuran (4 mL), andthe stirring was stopped to allow the excess zinc dust to settle down (2h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)(81 mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in drytetrahydrofuran (6 mL) was stirred at 25° C. under argon for 10 min andthen treated with1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.05 g, 3.5mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was heated at 40-45° C. over the weekend.The reaction mixture was cooled to 25° C. and then poured into asaturated aqueous ammonium chloride solution (50 mL), and the organiccompound was extracted into ethyl acetate (3×35 mL). The combinedorganic extracts were washed with a saturated aqueous sodium chloridesolution (1×100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid methyl ester (1.03 g, 77.6%) as a light yellow solid: EI-HRMS m/ecalcd for C₁₈H₁₉F₃N₄O₂ (M⁺) 380.1460, found 380.1453.

A solution of nickel (II) chloride hexahydrate (102 mg, 0.428 mmol) and(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid methyl ester (814 mg, 2.14 mmol) in methanol (20 mL) was cooled to0° C. and then treated with sodium borohydride (265 mg, 7 mmol) in fiveportions. After the addition, the black reaction mixture was stirred for15 min at 0° C. and then allowed to warm to 25° C. where it was stirredfor 15 h. The reaction mixture was concentrated in vacuo, and theresidue was diluted with a 3N aqueous hydrochloric acid solution (50 mL)and ethyl acetate (75 mL). The two layers were separated. The organiclayer was washed with a saturated aqueous sodium chloride solution (1×50mL), dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo to afford racemic3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd forC₁₈H₂₁F₃N₄O₂ (M⁺) 382.1617, found 382.1617.

A solution of3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid methyl ester (870 mg, 2.27 mmol) in ethanol (12 mL) was treatedwith a 1N aqueous sodium hydroxide solution (8 mL). The solution washeated at 45-50° C. for 3 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was concentrated in vacuo to removeethanol. The residue was diluted with water (50 mL) and extracted withdiethyl ether (1×60 mL) to remove any neutral impurities. The aqueouslayer was then acidified with a 1N aqueous hydrochloric acid solution,and the resulting acid was extracted into ethyl acetate (2×50 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to afford3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid (781 mg, 93%) as a white solid: EI-HRMS m/e calcd for C₁₇H₁₉F₃N₄O₂(M⁺) 368.1460, found 368.1460.

A solution of3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionicacid (368 mg, 1.0 mmol) in fluorobenzene (1.5 mL) andN,N-dimethylformamide (6 liL) at 25° C. was treated dropwise with oxalylchloride (107.7 μL, 1.21 mmol) over 2-3 min. The clear solution wasstirred for 1 h at 25° C. and then treated with methyl urea (322 mg, 2.0mmol). The resulting suspension was heated at 70° C. (bath temperature)for 10 min and then treated with pyridine (162 liL, 2.0 mmol). Thereaction mixture was then stirred at 70° C. for 20 h. The reactionmixture was then cooled to 25° C. and diluted with ethyl acetate (30 mL)and a 3N aqueous hydrochloric acid solution (30 mL). The two layers wereseparated, and the aqueous layer was extracted with ethyl acetate (1×20mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 1/1 to 1/2 hexanes/ethyl acetate)afforded1-{3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-urea(338 mg, 80%) as an amorphous white solid: EI-HRMS m/e calcd forC₁₉H₂₃F₃N₆O₂ (M⁺) 424.1834, found 424.1833.

EXAMPLE 111-{2-[3-Chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionyl}-3-methyl-urea

A suspension of triphenylphospine (11.7 g, 44.8 mmol) in carbontetrachloride (8 mL, 83 mmol) was cooled to 0° C. and then treated withtriethylamine (2.5 mL, 18 mmol) and acetic acid (1.15 mL, 20 mmol). Thereaction mixture was stirred at 0° C. for 10 min and then treated with asolution of 2-chloro-4-iodoaniline (5.07 g, 20 mmol) in carbontetrachloride (12 mL, heated to obtain a solution). The resulting lightbrown suspension was allowed to warm to 25° C. and then it was refluxedovernight. The reaction mixture was cooled to 25° C. and thenconcentrated in vacuo. The resulting solid residue was then diluted withhexanes (50 mL) and methylene chloride (50 mL). The precipitated solidwas collected by filtration and washed with hexanes. The filtrate wasconcentrated in vacuo, and the resulting residue was diluted withdiethyl ether (100 mL). The precipitated solid was collected byfiltration and washed with hexanes, and the filtrate was concentrated invacuo. The resulting residue was again diluted with hexanes (100 mL),and the precipitated solid was collected by filtration. The filtrate wasfinally concentrated in vacuo to afford the imidoyl chlorideintermediate (4.08 g) as a liquid. This crude imidoyl chlorideintermediate (4.08 g, ˜13 mmol) was treated with sodium azide (1.04 g,16 mmol) and acetic acid (10 mL). The reaction was exothermic, and theresulting reaction mixture was stirred for 1 h at 25° C. The reactionmixture was then heated at 70° C. for 2 h, at which time, thin layerchromatography analysis of the reaction mixture indicated the absence ofthe imidoyl chloride intermediate. The cloudy yellow suspension wascooled to 25° C. and then diluted with water (100 mL) and extracted withethyl acetate (2×75 mL). The combined organic extracts were washedsuccessively with a saturated aqueous sodium bicarbonate solution (1×100mL) and a saturated aqueous sodium chloride solution (1×100 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40M, Silica, 6/1 hexanes/diethyl ether)afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (350 mg, 6%)as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd for C₈H₆ClIN₄ (M⁺)319.9327, found 319.9325.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 nmmol). The zinc suspension was then heated with a heat gunto ebullition, allowed to cool, and heated again. This process wasrepeated three times to make sure the zinc dust was activated. Theactivated zinc dust suspension was then treated with trimethylsilylchloride (108 mg, 1 mmol), and the suspension was stirred for 15 min at25° C. The reaction mixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (prepared in Example10, 1.26 g, 4.5 mmol) in dry tetrahydrofuran (2 mL) over 3 min. Thereaction mixture was then stirred at 40-45° C. for 1 h and then stirredovernight at 25° C. The reaction mixture was then diluted with drytetrahydrofuran (3 mL), and the stirring was stopped to allow the excesszinc dust to settle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 Immol) andtriphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (4 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (875 mg, 2.73 mmol) andthe freshly prepared zinc compound in tetrahydrofuran. The resultingbrick red solution was stirred at 25° C. over the weekend and thenheated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C.and then poured into a saturated aqueous ammonium chloride solution (50mL), and the organic compound was extracted into ethyl acetate (3×35mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate)afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylicacid methyl ester (859 mg, 91%) as a light yellow semi-solid: EI-HRMSm/e calcd for C₁₇H₁₉ClN₄O₂ (M⁺) 346.1196, found 346.1190.

A solution of nickel (II) chloride hexahydrate (180 mg, 0.8 mmol) and(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)phenyl]-3-cyclopentyl-acrylicacid methyl ester (695 mg, 2.0 mmol) in methanol (15 mL) was cooled to0° C. and then treated with sodium borohydride (454 mg, 12 mmol) in fiveportions. After the addition, the black reaction mixture was stirred for15 min at 0° C. and then allowed to warm to 25° C. where it was stirredfor 2 d. The reaction mixture was concentrated in vacuo, and the residuewas diluted with a 3N aqueous hydrochloric acid solution (50 mL) andethyl acetate (75 mL). The two layers were separated. The organic layerwas washed with a saturated aqueous sodium chloride solution (1×50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo to afford racemic2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd forC₁₇H₂₁ClN₄O₂ (M⁺) 348.1353, found 348.1359.

A solution of2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid methyl ester ester (690 mg, 2.0 mmol) in ethanol (20 mL) wastreated with a 1N aqueous sodium hydroxide solution (4 mL). The solutionwas heated at 45-50° C. for 3 h, at which time, thin layerchromatography analysis of the reaction mixture indicated the absence ofstarting material. The reaction mixture was concentrated in vacuo toremove ethanol. The residue was diluted with water (50 mL) and extractedwith diethyl ether (1×60 mL) to remove any neutral impurities. Theaqueous layer was then acidified with a 1N aqueous hydrochloric acidsolution, and the resulting acid was extracted into ethyl acetate (2×50mL). The combined organic layers were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to afford2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid (604 mg, 90%) as an amorphous white solid: EI-HRMS m/e calcd forC₁₆H₁₉ClN₄O₂ (M⁺) 334.1196, found 334.1193.

A solution of2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionicacid (303 mg, 0.9 mmol) in fluorobenzene (1 mL) andN,N-dimethylformamide (3 μL) at 25° C. was treated dropwise with oxalylchloride (97 μL, 1.09 mmol) over 2-3 min. The clear solution was stirredat 25° C. for 1 h and then treated with methyl urea (201 mg, 2.72 mmol).The resulting suspension was heated at 70° C. (bath temperature) for 10min and then treated with pyridine (146.6 μL, 1.81 mmol). The reactionmixture was then stirred at 70° C. for 20 h. The reaction mixture wasthen cooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3Naqueous hydrochloric acid solution (30 mL). The two layers wereseparated, and the aqueous layer was extracted with ethyl acetate (1×20mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, I/1 hexanes/ethyl acetate) afforded1-{2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionyl}-3-methyl-urea(110 mg, 31%) as a white solid: mp 185-186° C. EI-HRMS m/e calcd forC₁₈H₂₃ClN₆O₂ (M+H)⁺ 391.1649, found 391.1659.

EXAMPLE 12(E)-3-Cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide

A solution of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred for 10 minat 0° C. and then was allowed to warm to 25° C. where it was stirred for2 h. After this time, thin layer chromatography analysis of the reactionmixture indicated the absence of starting material. The reaction mixturewas then concentrated in vacuo to afford a crude residue. The residueprecipitated from diethyl ether (50 mL) and hexanes (50 mL). The solidwas collected by filtration and washed with hexanes to affordN-(2-fluoro-4-iodo-phenyl)-acetamide (5.12 g, 92%) as a whitecrystalline solid: mp 152-154° C.; EI-HRMS m/e calcd for C₈H₇FINO (M⁺)278.9556, found 278.9559.

A suspension of N-(2-fluoro-4-iodo-phenyl)-acetamide (5.00 g, 18.24mmol) in acetonitrile (100 mL) was cooled to 0° C. and then treated withsodium azide (3.56 g, 54.7 mmol). The reaction mixture was then treatedwith trifluoromethanesulfonic anhydride (13.6 g, 48 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (100 mL) and water (100 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (1×50 mL). The combined organic extracts were washed with asaturated aqueous sodium chloride solution (1×100 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate)afforded 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (3.45 g, 62%)as a white solid: mp 122-124° C.; EI-HRMS m/e calcd for C₈H₆FIN₄ (M⁺)303.9621, found 303.9615.

A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (2.21 g, 7.5 mmol) indry tetrahydrofuran (3 mL) over 3 min. The resulting reaction mixturewas then stirred at 40-45° C. for 1 h and then stirred overnight at 25°C. The reaction mixture was then diluted with dry tetrahydrofuran (5mL), and the stirring was stopped to allow the excess zinc dust tosettle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (90 mg, 0.16 mnmol) andtriphenylphosphine (160 mg, 0.6 mmol) in dry tetrahydrofuran (10 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.52 g, 5 mmol) andthe freshly prepared zinc compound in tetrahydrofuran. The resultingbrick red solution was stirred at 25° C. over the weekend and thenheated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C.and then poured into a saturated aqueous ammonium chloride solution (50mL), and the organic compound was extracted into ethyl acetate (3×50mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate)afforded(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (1.14 g, 68%) as a light yellow solid: mp 111-114° C.;EI-HRMS m/e calcd for C₁₇H₁₉FN₄O₂ (M⁺) 330.1492, found 330.1493.

A solution of(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (720 mg, 2.18 mmol) in ethanol (15 mL) was treatedwith a 1N aqueous sodium hydroxide solution (5 mL). The solution washeated at 45-50° C. for 15 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was concentrated in vacuo to removeethanol. The residue was diluted with water (30 mL) and extracted withdiethyl ether (1×50 mL) to remove any neutral impurities. The aqueouslayer was then acidified with a 1N aqueous hydrochloric acid solution,and the resulting acid was extracted into ethyl acetate (2×50 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to afford(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (690 mg, 100%) as a white solid: mp 182-185° C.; EI-HRMS m/e calcdfor C₁₆H₁₇FN₄O₂ (M⁺) 316.1336, found 316.1334.

A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride(6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min andthen treated with(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (158 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h.The reaction mixture was then treated with 2-aminothiazole (150 mg, 1.5mmol), and the resulting suspension was stirred for 2 d at 25° C. Thereaction mixture was then concentrated in vacuo to remove methylenechloride, and the residue was diluted with ethyl acetate (20 mL) and a1N aqueous hydrochloric acid solution (30 mL). The two layers wereseparated, and the aqueous layer was extracted with ethyl acetate (1×15mL). The combined organic extracts were successively washed with a 1Naqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodiumbicarbonate solution (1×50 mL) and a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica,1/1 hexanes/ethyl acetate) afforded(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide(39 mg, 20%) as a white solid: mp 158-162° C.; EI-HRMS m/e calcd forC₁₉H₁₉FN₆OS (M⁺) 398.1325, found 398.1323.

EXAMPLE 13(E)-N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylamide

A solution of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred for 10 minat 0° C. and then was allowed to warm to 25° C. where it was stirred for2 h. After this time, thin layer chromatography analysis of the reactionmixture indicated the absence of starting material. The reaction mixturewas then concentrated in vacuo to afford a crude residue. The residueprecipitated from diethyl ether (50 mL) and hexanes (50 mL). The solidwas collected by filtration and washed with hexanes to affordN-(2-fluoro-4-iodo-phenyl)-acetamide (5.12 g, 92%) as a whitecrystalline solid: mp 152-154° C.; EI-HRMS m/e calcd for C₈H₇FINO (M⁺)278.9556, found 278.9559.

A suspension of N-(2-fluoro-4-iodo-phenyl)-acetamide (5.00 g, 18.24mmol) in acetonitrile (100 mL) was cooled to 0° C. and then treated withsodium azide (3.56 g, 54.7 mmol). The reaction mixture was then treatedwith trifluoromethanesulfonic anhydride (13.6 g, 48 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (100 mL) and water (100 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (1×50 mL). The combined organic extracts were washed with asaturated aqueous sodium chloride solution (1×100 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate)afforded 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (3.45 g, 62%)as a white solid: mp 122-124° C.; EI-HRMS m/e calcd for C₈H₆FIN₄ (M⁺)303.9621, found 303.9615.

A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (2.21 g, 7.5 mmol) indry tetrahydrofuran (3 mL) over 3 min. The resulting reaction mixturewas then stirred at 40-45° C. for 1 h and then stirred overnight at 25°C. The reaction mixture was then diluted with dry tetrahydrofuran (5mL), and the stirring was stopped to allow the excess zinc dust tosettle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (90 mg, 0.16 mmol) andtriphenylphosphine (160 mg, 0.6 mmol) in dry tetrahydrofuran (10 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.52 g, 5 mmol) andthe freshly prepared zinc compound in tetrahydrofuran. The resultingbrick red solution was stirred at 25° C. over the weekend and thenheated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C.and then poured into a saturated aqueous ammonium chloride solution (50mL), and the organic compound was extracted into ethyl acetate (3×50mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate)afforded(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (1.14 g, 68%) as a light yellow solid: mp 111-114° C.;EI-HRMS m/e calcd for C₁₇H₁₉FN₄O₂ (M⁺) 330.1492, found 330.1493.

A solution of(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (720 mg, 2.18 mmol) in ethanol (15 mL) was treatedwith a 1N aqueous sodium hydroxide solution (5 mL). The solution washeated at 45-50° C. for 15 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was concentrated in vacuo to removeethanol. The residue was diluted with water (30 mL) and extracted withdiethyl ether (1×50 mL) to remove any neutral impurities. The aqueouslayer was then acidified with a 1N aqueous hydrochloric acid solution,and the resulting acid was extracted into ethyl acetate (2×50 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to afford(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (690 mg, 100%) as a white solid: mp 182-185° C.; EI-HRMS m/e calcdfor C₁₆H₁₇FN₄O₂ (M⁺) 316.1336, found 316.1334.

A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride(6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min andthen treated with(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (158 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h.The reaction mixture was then treated with 2-amino-5-bromopyridine (260mg, 1.5 mmol), and the resulting suspension was stirred for 2 d at 25°C. The reaction mixture was then concentrated in vacuo to removemethylene chloride, and the residue was diluted with ethyl acetate (20mL) and water (30 mL). The two layers were separated, and the aqueouslayer was extracted with ethyl acetate (1×15 mL). The combined organicextracts were successively washed with a saturated aqueous sodiumbicarbonate solution (1×50 mL) and a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica,3/1 hexanes/ethyl acetate) afforded(E)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylamide(66 mg, 28%) as an amorphous white solid: EI-HRMS m/e calcd forC₂₁H₂₀BrFN₆OS (M⁺) 470.0866, found 470.0864.

EXAMPLE 14(E)-2-[3-Chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide

A solution of 2-chloro-4-iodoaniline (25 g, 96.66 mmol) intetrahydrofuran (100 mL) was cooled to 0° C. and then treated withacetic anhydride (50.6 g, 500 mmol). The reaction mixture was stirred at0° C. for 10 min and then allowed to warm to 25° C. where it was stirredfor 15 h. The reaction mixture was then concentrated in vacuo to removetetrahydrofuran. The residue was crystallized from ether (50 mL) andhexanes (50 mL). The solids were collected and washed with hexanes toafford N-(2-chloro-4-iodo-phenyl)-acetamide (23.87 g, 84%) as a whitecrystalline solid: EI-HRMS m/e calcd for C₈H₇ClINO (M⁺) 295.1526, found295.1532.

A suspension of N-(2-chloro-4-iodo-phenyl)-acetamide (2.39 g, 8.09 mmol)in acetonitrile (40 mL) at 25° C. was treated with methylene chloride (5mL) to obtain a clear solution. The resulting solution was then treatedwith sodium azide (1.05 g, 16.18 mmol), and the reaction mixture wascooled to 0° C. The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (3.42 g, 12.13 mmol), and theresulting reaction mixture was allowed to warm to 25° C. where it wasstirred overnight. The reaction mixture was then concentrated in vacuo.The residue was diluted with ethyl acetate (50 mL) and water (50 mL),and the two layers were separated. The aqueous layer was furtherextracted with ethyl acetate (1×30 mL). The combined organic layers werewashed with a saturated aqueous sodium chloride solution (1×100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethylacetate) afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.53g, 59%) as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd forC₈H₆ClIN₄ (M⁺) 319.9327, found 319.9325.

A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (1.26 g, 4.5 mmol) indry tetrahydrofuran (2 mL) over 3 min. The reaction mixture was thenstirred at 40-45° C. for 1 h and then stirred overnight at 25° C. Thereaction mixture was then diluted with dry tetrahydrofuran (3 mL), andthe stirring was stopped to allow the excess zinc dust to settle down(˜2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) andtriphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (4 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (875 mg, 2.73 mmol) andthe freshly prepared zinc compound in tetrahydrofuran. The resultingbrick red solution was stirred at 25° C. over the weekend and thenheated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C.and then poured into a saturated aqueous ammonium chloride solution (50mL), and the organic compound was extracted into ethyl acetate (3×35mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate)afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylicacid methyl ester (859 mg, 91%) as a light yellow semi-solid: EI-HRMSm/e calcd for C₁₇H₁₉ClN₄O₂ (M⁺) 346.1196, found 346.1190.

A solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylicacid methyl ester (160 mg, 0.46 mmol) in ethanol (5 mL) was treated witha 1N aqueous sodium hydroxide solution (1 mL). The solution was heatedat 45-50° C. for 15 h, at which time, thin layer chromatography analysisof the reaction mixture indicated the absence of starting material. Thereaction mixture was concentrated in vacuo to remove ethanol. Theresidue was diluted with water (10 mL) and extracted with diethyl ether(1×30 mL) to remove any neutral impurities. The aqueous layer was thenacidified with a 1N aqueous hydrochloric acid solution, and theresulting acid was extracted into ethyl acetate (2×20 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylicacid (155 mg, 100%) as a white solid: mp 216-219° C.; EI-HRMS m/e calcdfor C₁₆H₁₇ClN₄O₂ (M⁺) 332.1040, found 332.1048.

A solution of triphenylphosphine (165 mg, 0.63 inmol) in methylenechloride (5 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (112 mg, 0.63 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylicacid (123 mg, 0.37 mmol) in methylene chloride (3 mL). The reactionmixture was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 1.5 h. The reaction mixture was then treatedwith 2-aminothiazole (92.5 mg, 0.93 mmol), and the resulting suspensionwas stirred for 2 d at 25° C. The reaction mixture was then concentratedin vacuo to remove methylene chloride, and the residue was diluted withethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30mL). The two layers were separated, and the aqueous layer was extractedwith ethyl acetate (1×15 mL). The combined organic extracts weresuccessively washed with a 1N aqueous hydrochloric acid solution (1×50mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and asaturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate)afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide(36 mg, 23%) as an amorphous solid: EI-HRMS m/e calcd for C₁₉H₁₉ClN₆OS(M⁺) 414.1029, found 414.1029.

EXAMPLE 15(E)-2-[3-Chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide

A suspension of triphenylphospine (11.7 g, 44.8 mmol) in carbontetrachloride (8 mL, 83 mmol) was cooled to 0° C. and then treated withtriethylamine (2.5 mL, 18 mmol) and acetic acid (1.15 mL, 20 mmol). Thereaction mixture was stirred at 0° C. for 10 min and then treated with asolution of 2-chloro-4-iodoaniline (5.07 g, 20 mmol) in carbontetrachloride (12 mL, heated to obtain a solution). The resulting lightbrown suspension was allowed to warm to 25° C. and then it was refluxedovernight. The reaction mixture was cooled to 25° C. and thenconcentrated in vacuo. The resulting solid residue was then diluted withhexanes (50 mL) and methylene chloride (50 mL). The precipitated solidwas collected by filtration and washed with hexanes. The filtrate wasconcentrated in vacuo, and the resulting residue was diluted withdiethyl ether (100 mL). The precipitated solid was collected byfiltration and washed with hexanes, and the filtrate was concentrated invacuo. The resulting residue was again diluted with hexanes (100 mL),and the precipitated solid was collected by filtration. The filtrate wasfinally concentrated in vacuo to afford the imidoyl chlorideintermediate (4.08 g) as a liquid. This crude imidoyl chlorideintermediate (4.08 g, 13 mmol) was treated with sodium azide (1.04 g, 16mmol) and acetic acid (10 mL). The reaction was exothermic, and theresulting reaction mixture was stirred for lh at 25° C. The reactionmixture was then heated at 70° C. for 2 h, at which time, thin layerchromatography analysis of the reaction mixture indicated the absence ofthe imidoyl chloride intermediate. The cloudy yellow suspension wascooled to 25° C. and then diluted with water (100 mL) and extracted withethyl acetate (2×75 mL). The combined organic extracts were washedsuccessively with a saturated aqueous sodium bicarbonate solution (1×100mL) and a saturated aqueous sodium chloride solution (1×100 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40M, Silica, 6/1 hexanes/diethyl ether)afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (350 mg, 6%)as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd for C₈H₆ClIN₄ (M⁺)319.9327, found 319.9325.

A mixture of zinc dust (16.34 g, 250 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (6 mL) under argon was treated with 1,2-dibromoethane(0.94 g, 5 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (0.54 g, 5mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of cyclohexyl iodide(21 g, 100 mmol) in dry tetrahydrofuran (30 mL) over 15 min. During theaddition, the temperature rose to 60° C. The reaction mixture was thenstirred for 3 h at 40-45° C. The reaction mixture was then cooled to 25°C. and diluted with dry tetrahydrofuran (60 mL). The stirring wasstopped to allow the excess zinc dust to settle down (3 h). In aseparate reaction flask, a mixture of lithium chloride (8.48 g, 200mmol, predried at 130° C. under high vacuum for 3 h) and copper cyanide(8.95 g, 100 mmol) in dry tetrahydrofuran (110 mL) was stirred for 10min at 25° C. to obtain a clear solution. The reaction mixture wascooled to −70° C. and then slowly treated with the freshly prepared zincsolution using a syringe. After the addition, the reaction mixture wasallowed to warm to 0° C. where it was stirred for 5 min. The reactionmixture was again cooled back to −70° C. and then slowly treated withmethyl propiolate (7.56 g, 90 mmol). The resulting reaction mixture wasstirred for 15 h at −70° C. to −50° C. and then slowly treated with asolution of iodine (34.26 g, 135 mmol) in dry tetrahydrofuran (30 mL),with the temperature kept at −70° C. to −60° C. After addition of theiodine solution, the cooling bath was removed, and the reaction mixturewas allowed to warm to 25° C. where it was stirred for 2 h. The reactionmixture was then poured into a solution consisting of a saturatedaqueous ammonium chloride solution (400 mL) and ammonium hydroxide (100mL), and the organic compound was extracted into ethyl acetate (3×250mL). The combined organic extracts were successively washed with asaturated aqueous sodium thiosulfate solution (1×500 mL) and a saturatedaqueous sodium chloride solution (1×500 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/diethylether) afforded (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (26.3g, 99%) as a light pink oil: EI-HRMS m/e calcd for C₁₀H₁₅IO₂ (M⁺)294.0117, found 294.0114.

A mixture of zinc dust (320 mg, 5 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(94 mg, 0.5 mmol). The zinc suspension was then heated with a heat gunto ebullition, allowed to cool, and heated again. This process wasrepeated three times to make sure the zinc dust was activated. Theactivated zinc dust suspension was then treated with trimethylsilylchloride (55 mg, 0.5 mmol), and the suspension was stirred for 15 min at25° C. The reaction mixture was then treated dropwise with a solution of(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (588 mg, 2 mmol) indry tetrahydrofuran (2 mL). After the addition, the reaction mixture wasstirred for 1 h at 40-45° C. and then stirred overnight at 25° C. Thereaction mixture was then diluted with dry tetrahydrofuran (2 mL), andthe stirring was stopped to allow the excess zinc dust to settle down (2h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)(27 mg, 0.05 mmol) and triphenylphosphine (57 mg, 0.2 mmol) in drytetrahydrofuran (4 mL) was stirred at 25° C. under argon for 10 min andthen treated with 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole(320.5 mg, 1 mmol) and the freshly prepared zinc compound intetrahydrofuran. The resulting brick red solution was heated at 50° C.for 15 h. The reaction mixture was cooled to 25° C. and then poured intoa saturated aqueous ammonium chloride solution (30 mL), and the organiccompound was extracted into ethyl acetate (3×20 mL). The combinedorganic extracts were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica,4/1/1 hexanes/ethyl acetate/methylene chloride) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (233 mg, 64%) as an amorphous white solid: EI-HRMS m/ecalcd for C₁₈H₂₁ClN₄O₂ (M⁺) 360.1353, found 360.1354.

A solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (209 mg, 0.58 mmol) in ethanol (3 mL) was treated witha 1N aqueous sodium hydroxide solution (1.2 mL). The solution was heatedat 45-50° C. for 15 h, at which time, thin layer chromatography analysisof the mixture indicated the absence of starting material. The reactionmixture was then concentrated in vacuo to remove ethanol, and theresidue was diluted with water (10 mL) and extracted with diethyl ether(1×30 mL) to remove any neutral impurities. The aqueous layer wasacidified with a 1N aqueous hydrochloric acid solution. The resultingacid was extracted into ethyl acetate (2×20 mL). The combined organiclayers were washed with a saturated aqueous sodium chloride solution(1×50 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford(E)-2-[3chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid (203 mg, 99%) as a brown solid: FAB-HRMS m/e calcd for C₁₇H₁₉ClN₄O₂(M+H)⁺ 347.1275, found 347.1283.

A solution of triphenylphosphine (290 mg, 1.1 mmol) in methylenechloride (5 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (195 mg, 1.1 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid (192 mg, 0.55 mmol) in methylene chloride (3 mL). The reactionmixture was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 1.5 h. The reaction mixture was then treatedwith 2-aminothiazole (166 mg, 1.66 mmol), and the resulting suspensionwas stirred for 2 d at 25° C. The reaction mixture was concentrated invacuo to remove methylene chloride, and the residue was diluted withethyl acetate (40 mL) and a 1N aqueous hydrochloric acid solution (30mL). The two layers were separated, and the aqueous layer was extractedwith ethyl acetate (1×25 mL). The combined organic extracts weresuccessively washed with a 1N aqueous hydrochloric acid solution (1×50mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and asaturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 7/3 to 2/3 hexanes/ethylacetate) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide(86 mg, 36%) as an amorphous solid: EI-HRMS m/e calcd for C₂₀H₂₁ClN₆OS(M⁺) 428.1186, found 428.1189.

EXAMPLE 16(E)-2-[3-Chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide

A solution of 2-chloro-4-iodoaniline (25 g, 96.66 mmol) intetrahydrofuran (100 mL) was cooled to 0° C. and then treated withacetic anhydride (50.6 g, 500 mmol). The reaction mixture was stirred at0° C. for 10 min and then allowed to warm to 25° C. where it was stirredfor 15 h. The reaction mixture was then concentrated in vacuo to removetetrahydrofuran. The residue was crystallized from ether (50 mL) andhexanes (50 mL). The solids were collected and washed with hexanes toafford N-(2-chloro-4-iodo-phenyl)-acetamide (23.87 g, 84%) as a whitecrystalline solid: EI-HRMS m/e calcd for C₈H₇ClINO (M⁺) 295.1526, found295.1532.

A suspension of N-(2-chloro-4-iodo-phenyl)-acetamide (2.39 g, 8.09 mmol)in acetonitrile (40 mL) at 25° C. was treated with methylene chloride (5mL) to obtain a clear solution. The resulting solution was then treatedwith sodium azide (1.05 g, 16.18 mmol), and the reaction mixture wascooled to 0° C. The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (3.42 g, 12.13 mmol), and theresulting reaction mixture was allowed to warm to 25° C. where it wasstirred overnight. The reaction mixture was then concentrated in vacuo.The residue was diluted with ethyl acetate (50 mL) and water (50 mL),and the two layers were separated. The aqueous layer was furtherextracted with ethyl acetate (1×30 mL). The combined organic layers werewashed with a saturated aqueous sodium chloride solution (1×100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethylacetate) afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.53g, 59%) as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd forC₈H₆ClIN₄ (M⁺) 319.9327, found 319.9325.

A mixture of magnesium metal (4.81 g, 200 mmol) and dry tetrahydrofuran(10 mL) under argon treated with a solution of 1,2-dibromoethane (0.94g, 5 mmol) in dry tetrahydrofuran (5 mL). The resulting reaction mixturewas stirred for 10 min to activate the magnesium metal. The reactionmixture was then treated dropwise with a solution of cycloheptyl bromide(17.7 g, 100 mmol) in dry tetrahydrofuran (30 mL), one-fifth portionover a period of 5 min. The resulting reaction mixture was stirred for5-10 min to initiate the exothermic reaction. The remaining portion ofthe cycloheptyl bromide solution was then added dropwise whilecontrolling the inside temperature below 50° C. After complete addition,the solution was stirred for 1 h and then diluted with drytetrahydrofuran (80 mL). In a separate reaction flask, a mixture oflithium chloride (8.48 g, 200 mmol, predried at 130° C. under highvacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (110 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was cooled to −70° C. andthen slowly treated with the freshly prepared cycloheptylmagnesiumbromide. After the addition, the reaction mixture was allowed to warm to−10° C. where it was stirred for 5 min. The resulting reaction mixturewas again cooled back to −70° C. and then treated with methyl propiolate(7.57 g, 90 mmol). The reaction mixture was stirred for 15 h at −70° C.to −50° C. and then slowly treated with a solution of iodine (34.3 g,135 mmol) in dry tetrahydrofuran (30 mL), with the temperature kept at−70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(400 mL) and ammonium hydroxide (100 mL), and the organic compound wasextracted into ethyl acetate (3×200 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×400 mL) and a saturated aqueous sodium chloride solution(1×400 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 to 10/1 hexanes/diethyl ether)afforded (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (17.86 g,64%) as a colorless oil: EI-HRMS m/e calcd for C₁₁H₁₇IO₂ (M⁺) 308.0273,found 308.0273.

A mixture of zinc dust (980 mg, 15 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(280 mg, 1.5 mmol). The zinc suspension was then heated with a heat gunto ebullition, allowed to cool, and heated again. This process wasrepeated three times to make sure the zinc dust was activated. Theactivated zinc dust suspension was then treated with trimethylsilylchloride (162 mg, 1.5 mmol), and the suspension was stirred for 15 minat 25° C. The reaction mixture was then treated dropwise with a solutionof (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (1.54 g, 5 mmol)in dry tetrahydrofuran (3 mL). The reaction mixture was then stirred at40-45° C. for 1 h and then stirred overnight at 25° C. The reactionmixture was then diluted with dry tetrahydrofaran (5 mL), and thestirring was stopped to allow the excess zinc dust to settle down (2 h).In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (81mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in drytetrahydrofuran (12 mL) was stirred at 25° C. under argon for 10 min andthen treated with 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.28g, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran.The resulting brick red solution was heated at 45-50° C. for 20 h. Thereaction mixture was cooled to 25° C. and then poured into a saturatedaqueous ammonium chloride solution (100 mL), and the organic compoundwas extracted into ethyl acetate (3×50 mL). The combined organicextracts were washed with a saturated aqueous sodium chloride solution(1×100 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to1/1 hexanes/ethyl acetate) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid methyl ester (1.29 g, 85%) as a yellow oil: EI-HRMS m/e calcd forC₁₉H₂₃ClN₄O₂ (M⁺) 374.1509, found 374.1509.

A solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid methyl ester (1.20 g, 3.2 mmol) in ethanol (15 mL) was treated witha 1N aqueous sodium hydroxide solution (6.5 mL). The solution was heatedat 45-50° C. for 15 h, at which time, thin layer chromatography analysisof the reaction mixture indicated the absence of starting material. Thereaction mixture was concentrated in vacuo to remove ethanol. Theresidue was diluted with water (50 mL) and extracted with diethyl ether(1×50 mL) to remove any neutral impurities. The aqueous layer was thenacidified with a 1N aqueous hydrochloric acid solution, and theresulting acid was extracted into ethyl acetate (2×70 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid (1.01 g, 87%) as a white solid.

A solution of triphenylphosphine (1.45 g, 5.54 mmol) in methylenechloride (15 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (986 mg, 5.54 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid (1.00 g, 2.77 mmol) in methylene chloride (5 mL). The reactionmixture was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 1.5 h. The reaction mixture was then treatedwith 2-aminothiazole (832 g, 8.32 inmol), and the resulting suspensionwas stirred for 3 d at 25° C. The reaction mixture was then concentratedin vacuo to remove methylene chloride, and the residue was diluted withethyl acetate (50 mL) and water (50 mL). The two layers were separated,and the aqueous layer was extracted with ethyl acetate (1×50 mL). Thecombined organic extracts were successively washed with a saturatedaqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide(810 mg, 66%) as an amorphous white solid: EI-HRMS m/e calcd forC₂₁H₂₃ClN₆OS (M⁺) 442.1343, found 442.1343.

EXAMPLE 17(E)-N-(5-Bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylamide

A solution of 2-chloro-4-iodoaniline (25 g, 96.66 mm0l) intetrahydrofuran (100 mL) was cooled to 0° C. and then treated withacetic anhydride (50.6 g, 500 mmol). The reaction mixture was stirred at0° C. for 10 min and then allowed to warm to 25° C. where it was stirredfor 15 h. The reaction mixture was then concentrated in vacuo to removetetrahydrofaran. The residue was crystallized from ether (50 mL) andhexanes (50 mL). The solids were collected and washed with hexanes toafford N-(2-chloro-4-iodo-phenyl)-acetamide (23.87 g, 84%) as a whitecrystalline solid: EI-HRMS m/e calcd for C₈H₇ClINO (M⁺) 295.1526, found295.1532.

A suspension of N-(2-chloro-4-iodo-phenyl)-acetamide (2.39 g, 8.09 mmol)in acetonitrile (40 mL) at 25° C. was treated with methylene chloride (5mL) to obtain a clear solution. The resulting solution was then treatedwith sodium azide (1.05 g, 16.18 mmol), and the reaction mixture wascooled to 0° C. The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (3.42 g, 12.13 mmol), and theresulting reaction mixture was allowed to warm to 25° C. where it wasstirred overnight. The reaction mixture was then concentrated in vacuo.The residue was diluted with ethyl acetate (50 mL) and water (50 mL),and the two layers were separated. The aqueous layer was furtherextracted with ethyl acetate (1×30 mL). The combined organic layers werewashed with a saturated aqueous sodium chloride solution (1×100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethylacetate) afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.53g, 59%) as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd forC₈H₆ClIN₄ (M⁺) 319.9327, found 319.9325.

A mixture of magnesium metal (4.81 g, 200 mmol) and dry tetrahydrofuran(10 mL) under argon was treated with a solution of 1,2-dibromoethane(0.94 g, 5 mmol) in dry tetrahydrofuran (5 mL). The resulting reactionmixture was stirred for 10 min to activate the magnesium metal. Thereaction mixture was then treated dropwise with a solution ofcycloheptyl bromide (17.7 g, 100 mmol) in dry tetrahydrofuran (30 mL),one-fifth portion over a period of 5 min. The resulting reaction mixturewas stirred for 5-10 min to initiate the exothermic reaction. Theremaining portion of the cycloheptyl bromide solution was then addeddropwise while controlling the inside temperature below 50° C. Aftercomplete addition, the solution was stirred for 1 h and then dilutedwith dry tetrahydrofuran (80 mL). In a separate reaction flask, amixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C. underhigh vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (110 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was cooled to −70° C. andthen slowly treated with the freshly prepared cycloheptylmagnesiumbromide. After the addition, the reaction mixture was allowed to warm to−10° C. where it was stirred for 5 min. The resulting reaction mixturewas again cooled back to −70° C. and then treated with methyl propiolate(7.57 g, 90 mmol). The reaction mixture was stirred for 15 h at −70° C.to −50° C. and then slowly treated with a solution of iodine (34.3 g,135 mmol) in dry tetrahydrofuran (30 mL), with the temperature kept at−70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(400 mL) and ammonium hydroxide (100 mL), and the organic compound wasextracted into ethyl acetate (3×200 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×400 mL) and a saturated aqueous sodium chloride solution(1×400 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 to 10/1 hexanes/diethyl ether)afforded (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (17.86 g,64%) as a colorless oil: EI-HRMS m/e calcd for C₁₁H₁₇IO₂ (M⁺) 308.0273,found 308.0273.

A mixture of zinc dust (980 mg, 15 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(280 mg, 1.5 mmol). The zinc suspension was then heated with a heat gunto ebullition, allowed to cool, and heated again. This process wasrepeated three times to make sure the zinc dust was activated. Theactivated zinc dust suspension was then treated with trimethylsilylchloride (162 mg, 1.5 mmol), and the suspension was stirred for 15 minat 25° C. The reaction mixture was then treated dropwise with a solutionof (E)-3-cycloheptyl-2-iode-acrylic acid methyl ester (1.54 g, 5 mmol)in dry tetrahydrofuran (3 mL). The reaction mixture was then stirred at40-45° C. for 1 h and then stirred overnight at 25° C. The reactionmixture was then diluted with dry tetrahydrofuran (5 mL), and thestirring was stopped to allow the excess zinc dust to settle down (2 h).In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (81mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in drytetrahydrofuran (12 mL) was stirred at 25° C. under argon for 10 min andthen treated with 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.28g, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran.The resulting brick red solution was heated at 45-50° C. for 20 h. Thereaction mixture was cooled to 25° C. and then poured into a saturatedaqueous ammonium chloride solution (100 mL), and the organic compoundwas extracted into ethyl acetate (3×50 mL). The combined organicextracts were washed with a saturated aqueous sodium chloride solution(1×100 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to1/1 hexanes/ethyl acetate) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid methyl ester (1.29 g, 85%) as a yellow oil: EI-HRMS m/e calcd forC₁₉H₂₃ClN₄O₂ (M⁺) 374.1509, found 374.1509.

A solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid methyl ester (1.20 g, 3.2 mmol) in ethanol (15 mL) was treated witha 1N aqueous sodium hydroxide solution (6.5 mL). The solution was heatedat 45-50° C. for 15 h, at which time, thin layer chromatography analysisof the reaction mixture indicated the absence of starting material. Thereaction mixture was concentrated in vacuo to remove ethanol. Theresidue was diluted with water (50 mL) and extracted with diethyl ether(1×50 mL) to remove any neutral impurities. The aqueous layer was thenacidified with a 1N aqueous hydrochloric acid solution, and theresulting acid was extracted into ethyl acetate (2×70 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid (1.01 g, 87%) as a white solid.

A solution of triphenylphosphine (1.45 g, 5.54 mmol) in methylenechloride (15 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (986 mg, 5.54 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylicacid (1.00 g, 2.77 mmol) in methylene chloride (5 mL). The reactionmixture was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 1.5 h. The reaction mixture was then treatedwith 2-aminothiazole (832 g, 8.32 mmol), and the resulting suspensionwas stirred for 3 d at 25° C. The reaction mixture was then concentratedin vacuo to remove methylene chloride, and the residue was diluted withethyl acetate (50 mL) and water (50 mL). The two layers were separated,and the aqueous layer was extracted with ethyl acetate (1×50 mL). Thecombined organic extracts were successively washed with a saturatedaqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide(810 mg, 66%) as an amorphous white solid: EI-HRMS m/e calcd forC₂₁H₂₃ClN₆OS (M⁺) 442.1343, found 442.1343.

A suspension of(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide(300 mg, 0.69 mmol) and N-bromosuccinimide (123 mg, 0.69 mmol) in carbontetrachloride (3 mL) at 25° C. was treated with benzoyl peroxide (8.4mg, 0.035 mmol). The resulting reaction mixture was heated to 90° C.where it was stirred overnight at this temperature. The reaction mixturewas allowed to cool to 25° C. and then concentrated in vacuo. Theresidue was dissolved in ethyl acetate (50 mL). The organic phase wasthen washed with water (1×50 mL) and a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica,4/1 hexanes/ethyl acetate) afforded(E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3cycloheptyl-acrylamide(118 mg, 33%) as an amorphous solid: EI-HRMS m/e calcd forC₂₁H₂₂BrClN₆OS (M⁺) 520.0448, found 520.0448.

EXAMPLE 18(E)-2-[-Chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide

A suspension of triphenylphospine (13.11 g, 50 mmol) in carbontetrachloride (8 mL, 83 mmol) was cooled to 0° C. and then treated withtriethylamine (2.78 mL, 20 mmol) and trifluoroacetic acid (1.3 mL, 16.6mmol). The reaction mixture was stirred at 0° C. for 10 min and thentreated with a solution of 2-chloro-4-iodoaniline (5.07 g, 20 mmol) incarbon tetrachloride (10 mL). The resulting light brown suspension wasallowed to warm to 25° C. and then it was refluxed overnight. Thereaction mixture was cooled to 25° C. and then concentrated in vacuo.The resulting solid residue was then diluted with hexanes (50 mL) andmethylene chloride (50 mL). The precipitated solid was collected byfiltration and washed with hexanes. The filtrate was concentrated invacuo, and the resulting residue was diluted with diethyl ether (100mL). The precipitated solid was collected by filtration and washed withhexanes, and the filtrate was concentrated in vacuo. The resultingresidue was again diluted with hexanes (100 mL), and the precipitatedsolid was collected by filtration. The filtrate was finally concentratedin vacuo to afford the imidoyl chloride intermediate (5.88 g) as a brownliquid. This crude imidoyl chloride intermediate (5.88 g, 16 mmol) wastreated with sodium azide (1.04 g, 16 mmol) and acetic acid (10 mL). Theresulting reaction mixture was then heated at 70° C. for 2 h, at whichtime, thin layer chromatography analysis of the reaction mixtureindicated the absence of the imidoyl chloride intermediate. The cloudyyellow suspension was cooled to 25° C. and then diluted with water (100mL) and extracted with ethyl acetate (2×75 mL). The combined organicextracts were washed successively with a saturated aqueous sodiumbicarbonate solution (1×100 mL) and a saturated aqueous sodium chloridesolution (1×100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica,8/1 hexanes/diethyl ether) afforded1-(2-chloro-4-iodo-phenyl)-5-trifluoromethyl-1H-tetrazole (5.2 g, 69%)as a light yellow solid: mp 71-73° C.; EI-HRMS m/e calcd for C₈H₃ClF₃IN₄(M⁺) 373.9043, found 373.9044.

A mixture of zinc dust (16.34 g, 250 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (6 mL) under argon was treated with 1,2-dibromoethane(0.94 g, 5 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (0.54 g, 5mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of cyclohexyl iodide(21 g, 100 mmol) in dry tetrahydrofuran (30 mL) over 15 min. During theaddition, the temperature rose to 60° C. The reaction mixture was thenstirred for 3 h at 40-45° C. The reaction mixture was then cooled to 25°C. and diluted with dry tetrahydrofuran (60 mL). The stirring wasstopped to allow the excess zinc dust to settle down (3 h). In aseparate reaction flask, a mixture of lithium chloride (8.48 g, 200mmol, predried at 130° C. under high vacuum for 3 h) and copper cyanide(8.95 g, 100 mmol) in dry tetrahydrofuran (110 mL) was stirred for 10min at 25° C. to obtain a clear solution. The reaction mixture wascooled to −70° C. and then slowly treated with the freshly prepared zincsolution using a syringe. After the addition, the reaction mixture wasallowed to warm to 0° C. where it was stirred for 5 min. The reactionmixture was again cooled back to −70° C. and then slowly treated withmethyl propiolate (7.56 g, 90 mmol). The resulting reaction mixture wasstirred for 15 h at −70° C. to −50° C. and then slowly treated with asolution of iodine (34.26 g, 135 mmol) in dry tetrahydrofuran (30 mL),with the temperature kept at −70° C. to −60° C. After addition of theiodine solution, the cooling bath was removed, and the reaction mixturewas allowed to warm to 25° C. where it was stirred for 2 h. The reactionmixture was then poured into a solution consisting of a saturatedaqueous ammonium chloride solution (400 mL) and ammonium hydroxide (100mL), and the organic compound was extracted into ethyl acetate (3×250mL). The combined organic extracts were successively washed with asaturated aqueous sodium thiosulfate solution (1×500 mL) and a saturatedaqueous sodium chloride solution (1×500 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/diethylether) afforded (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (26.3g, 99%) as a light pink oil: EI-HRMS m/e calcd for C₁₀H₁₅IO₂ (M⁺)294.0117, found 294.0114.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (2 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (110 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (1.32 g, 4.5 mmol) indry tetrahydrofuran (2 mL) over 5 min. After the addition, the reactionmixture was stirred for 1 h at 40-45° C. and then stirred overnight at25° C. The reaction mixture was then diluted with dry tetrahydrofuran (4mL), and the stirring was stopped to allow the excess zinc dust tosettle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) andtriphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (8 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-chloro-4-iodo-phenyl)-5-trifluoromethyl-1H-tetrazole (1.12 g, 3mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was heated at 50° C. for 15 h. The reactionmixture was cooled to 25° C. and then poured into a saturated aqueousammonium chloride solution (70 mL), and the organic compound wasextracted into ethyl acetate (3×50 mL). The combined organic extractswere washed with a saturated aqueous sodium chloride solution (1×100mL), dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 hexanes/ethylacetate) afforded the(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (908 mg, 73%) as an amorphous white solid: EI-HRMS m/ecalcd for C₁₈H₁₈ClF₃N₄O₂ (M⁺) 414.1070, found 414.1075.

A solution of(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid methyl ester (833 mg, 2 mmol) in ethanol (10 mL) was treated with a1N aqueous sodium hydroxide solution (4 mL). The solution was heated at45-50° C. for 15 h, at which time, thin layer chromatography analysis ofthe mixture indicated the absence of starting material. The reactionmixture was then concentrated in vacuo to remove ethanol, and theresidue was diluted with water (20 mL) and extracted with diethyl ether(1×50 mL) to remove any neutral impurities. The aqueous layer wasacidified with a 1N aqueous hydrochloric acid solution. The resultingacid was extracted into ethyl acetate (2×50 mL). The combined organiclayers were washed with a saturated aqueous sodium chloride solution(1×100 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid (606 mg, 75%) as a brown solid: FAB-HRMS m/e calcd forC₁₇H₁₆ClF₃N₄O₂ (M+H)⁺ 401.0992, found 401.0987.

A solution of triphenylphosphine (772 mg, 2.96 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (526 mg, 2.96 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylicacid (594 mg, 1.48 mmol) in methylene chloride (5 mL). The reactionmixture was then stirred for 15 min at 0° C. and then allowed to warm to25° C. where it was stirred for 1.5 h. The reaction mixture was thentreated with 2-aminothiazole (444 mg, 4.44 mmol), and the resultingsuspension was stirred for 2 d at 25° C. The reaction mixture wasconcentrated in vacuo to remove methylene chloride, and the residue wasdiluted with ethyl acetate (70 mL) and a 1N aqueous hydrochloric acidsolution (50 mL). The two layers were separated, and the aqueous layerwas extracted with ethyl acetate (1×50 mL). The combined organicextracts were successively washed with a 1N aqueous hydrochloric acidsolution (1×100 mL), a saturated aqueous sodium bicarbonate solution(1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 to 3/2hexanes/ethyl acetate) afforded(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide(82 mg, 11%) as an amorphous solid: EI-HRMS m/e calcd for C₂₀H₁₈ClF₃N₆OS(M⁺) 482.0903, found 482.0906.

EXAMPLE 19(E)-3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-acrylamide

A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0° C.for 10 min and then allowed to warm to 25° C. The reaction mixture wasstirred at 25° C. for 2 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was then concentrated in vacuo. The cruderesidue precipitated from diethyl ether (50 mL) and hexanes (50 mL). Thesolid was collected by filtrated and washed with hexanes to affordN-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as anamorphous white solid: EI-HRMS m/e calcd for C₉H₇BrF₃NO (M⁺) 281.8352,found 281.8348.

A suspension of N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (2.41 g,8.54 mmol) in acetonitrile (40 mL) was treated with methylene chloride(5 mL) to obtain a clear solution at 25° C. The resulting solution wastreated with sodium azide (1.24 g, 19.1 mmol), and the reaction mixturewas then cooled to 0° C. The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (3.59 g, 12.7 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (50 mL) and water (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×30 mL). The combined organic extracts were washed with a saturatedaqueous sodium chloride solution (1×100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.85 g, 70%)as a white solid: EI-HRMS m/e calcd for C₉H₆BrF₃N₄ (M⁺) 305.9728, found305.9733.

A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (710 mg, 11 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (1.54 g, 5.5 mmol) indry tetrahydrofuran (2 mL) over 3 min. The reaction mixture was thenstirred at 40-45° C. for 1 h and then stirred overnight at 25° C. Thereaction mixture was then diluted with dry tetrahydrofuran (4 mL), andthe stirring was stopped to allow the excess zinc dust to settle down (2h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)(81 mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in drytetrahydrofuran (6 mL) was stirred at 25° C. under argon for 10 min andthen treated with1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.05 g, 3.5mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was heated at 40-45° C. over the weekend.The reaction mixture was cooled to 25° C. and then poured into asaturated aqueous ammonium chloride solution (50 mL), and the organiccompound was extracted into ethyl acetate (3×35 mL). The combinedorganic extracts were washed with a saturated aqueous sodium chloridesolution (1×100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid methyl ester (1.03 g, 77.6%) as a light yellow solid: EI-HRMS m/ecalcd for C₁₈H₁₉F₃N₄O₂ (M⁺) 380.1460, found 380.1453.

A solution of(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid methyl ester (199 mg, 0.52 mmol) in ethanol (3 mL) was treated witha 1N aqueous sodium hydroxide solution (2 mL). The solution was heatedat 45-50° C. for 15 h, at which time, thin layer chromatography analysisof the reaction mixture indicated the absence of starting material. Thereaction mixture was concentrated in vacuo to remove ethanol. Theresidue was diluted with water (10 mL) and extracted with diethyl ether(1×30 mL) to remove any neutral impurities. The aqueous layer was thenacidified with a 1N aqueous hydrochloric acid solution, and theresulting acid was extracted into ethyl acetate (2×20 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid (172 mg, 90%) as a yellow paste: EI-HRMS m/e calcd for C₁₇H₁₇F₃N₄O₂(M⁺) 366.1309, found 366.1309.

A solution of triphenylphosphine (204 mg, 0.78 mmol) in methylenechloride (8 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (138 mg, 0.78 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylicacid (143 mg, 0.39 mmol) in methylene chloride (5 mL). The reactionmixture was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 1.5 h. The reaction mixture was then treatedwith 2-aminothiazole (117 mg, 1.17 mmol), and the resulting suspensionwas stirred for 2 d at 25° C. The reaction mixture was then concentratedin vacuo to remove methylene chloride, and the residue was diluted withethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30mL). The two layers were separated, and the aqueous layer was extractedwith ethyl acetate (1×15 mL). The combined organic extracts weresuccessively washed with a 1N aqueous hydrochloric acid solution (1×50mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and asaturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 1/2 hexanes/ethyl acetate)afforded the(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-acrylamide(27 mg, 15.5%) as an amorphous white solid: EI-HRMS m/e calcd forC₂₀H₁₉F₃N₆OS (M⁺) 448.1293, found 448.1285.

EXAMPLE 20(E)-3-Cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide

A solution of 2-nitro-4-bromoaniline (7.07 g, 32.6 mmol) in drytetrahydrofuran (33 mL) was cooled to 0° C. and then treated with aceticanhydride (6.66 g, 65.2 mmol). The reaction mixture was stirred at 0° C.for 10 min and then allowed to warm to 25° C. The reaction mixture wasstirred at 25° C. for 15 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the presence of only startingmaterial. The reaction mixture was then slowly treated with acetylchloride (5 mL) and pyridine (5 mL) at 25° C. The resulting orangesuspension was stirred at 25° C. for 2 h and then treated with water (50mL). The organic compound was extracted into ethyl acetate (2×70 mL).The combined extracts were washed with a 3N aqueous hydrochloric acidsolution (1×100 mL) and a saturated aqueous sodium chloride solution(1×100 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford a yellow solid. The yellow solid wastreated with diethyl ether (50 mL) and hexanes (50 mL). The solid wascollected by filtration and washed with hexanes to affordN-(4-bromo-2-nitro-phenyl)-acetamide (6.82 g, 81%) as a yellow solid: mp100-102° C.; EI-HRMS m/e calcd for C₈H₇BrN₂O₃ (M⁺) 257.9640, found257.9641.

A suspension of N-(4-bromo-2-nitro-phenyl)-acetamide (1.18 g, 4.55 mmol)in acetonitrile (25 mL) was cooled to 0° C. and then treated with sodiumazide (838 mg, 13.65 mmol). The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (2.88 g, 10.25 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (70 mL) and water (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×50 mL). The combined organic extracts were washed with a saturatedaqueous sodium chloride solution (1×100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded1-(4-bromo-2-nitro-phenyl)-5-methyl-1H-tetrazole (1.16 g, 90%) as awhite solid: mp 124-126° C.; EI-HRMS m/e calcd for C₈H₆BrN₅O₂ (M⁺)282.9705, found 282.9700.

A suspension of 1-(4-bromo-2-nitro-phenyl)-5-methyl-IH-tetrazole (1.13g, 3.98 mmol) in methanol (40 mL, not completely dissolved in methanoleven at hot conditions) was treated sequentially with ammonium chloride(3.19 g, 59.7 mmol), zinc dust (2.60 g, 39.8 mmol), and water (20 mL).Initially after the addition, the reaction was exothermic. The reactionmixture was then stirred for 1 h at 25° C. The reaction mixture was thenfiltered, and the residue was washed with methanol (50 mL) and ethylacetate (100 mL). The filtrate was concentrated in vacuo, and theorganic compound was extracted into ethyl acetate (3×50 mL). Thecombined organic extracts were washed with a saturated aqueous sodiumchloride solution (1×200 mL), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford5-bromo-2-(5-methyl-tetrazol-1-yl)-phenylamine 0.90 g, 97%) as a whitesolid EI-HRMS m/e calcd for C₈H₈BrN₅ (M⁺) 252.9963, found 252.9962.

A solution of isoamyl nitrite (402 μL, 3 mmol) in dimethyl disulfide (2mL, 22 mmol) at 25° C. was slowly treated with5-bromo-2-(5-methyl-tetrazol-1-yl)-phenylamine (0.51 g, 2 mmol). Thereaction was exothermic with gas evolution. The resulting brown reactionmixture was heated to 80-90° C. for 2 h, at which time, thin layerchromatography analysis of the reaction mixture indicated the absence ofstarting material. The reaction mixture was cooled to 25° C. and thenconcentrated in vacuo. The resulting residue was dissolved in ethylacetate (50 mL). The organic layer was washed successively with a 1Naqueous hydrochloric acid solution (1×50 mL) and a saturated aqueoussodium chloride solution (1×50 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(FLASH 40M, Silica, 6/1 to 5/1 hexanes/ethyl acetate) afforded1-(4-bromo-2-methylsulfanyl-phenyl)-5-methyl-1H-tetrazole (0.8 g) as abrown solid that was used without further purification andcharacterization.

A solution of 1-(4-bromo-2-methylsulfanyl-phenyl)-5-methyl-1H-tetrazole(0.8 g, ˜2 mmol) in methylene chloride (12 mL) was cooled to −10° C. andthen treated with 3-chloroperoxybenzoic acid (86% grade, 2.0 g, 12mmol). The reaction mixture was stirred at −10° C. for 10 min and thenallowed to warm to 25° C. where it was stirred over the weekend. At thistime, thin layer chromatography analysis of the reaction mixtureindicated the absence of starting material. The reaction mixture wasthen concentrated in vacuo. The resulting residue was dissolved in ethylacetate (60 mL). The organic layer was washed successively with asaturated aqueous sodium bicarbonate solution (2×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to afford ayellow solid. Biotage chromatography (FLASH 40M, Silica, 3/1hexanes/ethyl acetate) afforded1-(4-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (313 mg, 49%)as a white solid: mp 175-176° C.; EI-HRMS m/e calcd for C₉H₉BrN₄O₂S (M⁺)315.9630, found 315.9630.

A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (330 mg, 5 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (440 mg, 1.5 mmol) indry tetrahydrofuran (1 mL). The resulting reaction mixture was thenstirred at 40-45° C. for 1 h and then stirred overnight at 25° C. Thereaction mixture was then diluted with dry tetrahydrofuran (3 mL), andthe stirring was stopped to allow the excess zinc dust to settle down (2h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)(27 mg, 0.05 mmol) and triphenylphosphine (52 mg, 0.2 mmol) in drytetrahydrofuran (4mL) was stirred at 25° C. under argon for 10 min andthen treated with1-(4-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (297 mg, 0.94mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was stirred at 4045° C. over the weekend.The reaction mixture was cooled to 25° C. and then poured into asaturated aqueous ammonium chloride solution (30 mL), and the organiccompound was extracted into ethyl acetate (3×25 mL). The combinedorganic extracts were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica,4/1 to 1/1 hexanes/ethyl acetate) afforded(E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (289 mg, 78%) as an amorphous yellow solid: EI-HRMSm/e calcd for C₁₈H₂₂N₄O₄S (M⁺) 390.1362, found 390.1363.

A solution of (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (273 mg, 0.7mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxidesolution (1.5 mL). The solution was heated at 45-50° C. for 15 h, atwhich time, thin layer chromatography analysis of the reaction mixtureindicated the absence of starting material. The reaction mixture wasconcentrated in vacuo to remove ethanol. The residue was diluted withwater (20 mL) and extracted with diethyl ether (1×30 mL) to remove anyneutral impurities. The aqueous layer was then acidified with a 1Naqueous hydrochloric acid solution, and the resulting acid was extractedinto ethyl acetate (2×30 mL). The combined organic layers were washedwith a saturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford(E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (262 mg, 100%) as a yellow solid: EI-HRMS m/e calcd for C₁₇H₂₀N₄O₄S(M⁺) 376.1205, found 376.1204.

A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride(6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min andthen treated with(E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (190 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h.The reaction mixture was then treated with 2-aminothiazole (250 mg, 2.5mmol), and the resulting suspension was stirred for 2 d at 25° C. Thereaction mixture was then concentrated in vacuo to remove methylenechloride, and the residue was diluted with ethyl acetate (20 mL) andwater (30 mL). The two layers were separated, and the aqueous layer wasextracted with ethyl acetate (1×15 mL). The combined organic extractswere successively washed with a saturated aqueous sodium bicarbonatesolution (1×50 mL) and a saturated aqueous sodium chloride solution(1×50 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1hexanes/ethyl acetate) afforded(E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide(42 mg, 18%) as an amorphous white solid: EI-HRMS m/e calcd forC₂₁H₂₂N₆O₃S₂ (M⁺) 458.1195, found 458.1192.

EXAMPLE 21(E)-4-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoicacid thiazol-2-ylamide

A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0° C.for 10 min and then allowed to warm to 25° C. The reaction mixture wasstirred at 25° C. for 2 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was then concentrated in vacuo. The cruderesidue precipitated from diethyl ether (50 mL) and hexanes (50 mL). Thesolid was collected by filtrated and washed with hexanes to affordN-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as anamorphous white solid: EI-HRMS m/e calcd for C₉H₇BrF₃NO (M⁺) 281.8352,found 281.8348.

A suspension of N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (2.41 g,8.54 mmol) in acetonitrile (40 mL) was treated with methylene chloride(5 mL) to obtain a clear solution at 25° C. The resulting solution wastreated with sodium azide (1.24 g, 19.1 mmol), and the reaction mixturewas then cooled to 0° C. The reaction mixture was then treated withtrifluoromethanesulfonic anhydride (3.59 g, 12.7 nmmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (50 mL) and water (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×30 mL). The combined organic extracts were washed with a saturatedaqueous sodium chloride solution (1×100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.85 g, 70%)as a white solid: EI-HRMS m/e calcd for C₉H₆BrF₃N₄ (M⁺) 305.9728, found305.9733.

A mixture of zinc dust (3.92 g, 60 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (4 mL) under argon was treated with 1,2-dibromoethane(0.56 g, 3 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (0.32 g, 3nmmol, and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of cyclopentylmethyliodide (4.2 g, 20 mmol) in dry tetrahydrofuran (7 mL) over 5 min. Duringthe addition, the temperature rose to 50° C., and the reaction mixturewas stirred overnight at 40-45° C. The reaction mixture was then cooledto 25° C. and diluted with dry tetrahydrofuran (5 mL). The stirring wasstopped to allow the excess zinc dust to settle down (˜2 h). In aseparate reaction flask, a mixture of lithium chloride (1.7 g, 40 mmol,predried at 130° C. under high vacuum for 2 h) and copper cyanide (1.79g, 20 mmol) in dry tetrahydrofuran (20 mL) was stirred for 10 min at 25°C. to obtain a clear solution. The reaction mixture was cooled to −70°C. and then the slowly treated with the freshly prepared zinc solutionusing a syringe. After the addition, the reaction mixture was allowed towarm to −30° C., where it was stirred for 5 min. The reaction mixturewas again cooled back to −70° C. and then slowly treated with methylpropiolate (1.52 g, 18 mmol). The reaction mixture was stirred for 4 hat −40° C. to −30° C. and then slowly treated with a solution of iodine(6.85 g, 27 mmol) in dry tetrahydrofuran (10 mL), with the temperaturekept at −70° C. to −60° C. After the addition of the iodine solution,the cooling bath was removed, and the reaction mixture was allowed towarm to 25° C. where it was stirred for 1 h. The reaction mixture wasthen poured into a solution consisting of a saturated aqueous ammoniumchloride solution (90 mL) and ammonium hydroxide (10 mL), and theorganic compound was extracted into diethyl ether (3×50 mL). Thecombined ether extracts were successively washed with a saturatedaqueous sodium thiosulfate solution (1×100 mL) and a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtrated, and concentrated in vacuo. Biotage chromatography(FLASH 40M, Silica, 9/1 hexanes/diethyl ether) afforded(E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester (4.56 g, 86%) asa colorless oil: EI-HRMS m/e calcd for C₁₀H,₅IO₂ (M⁺) 294.0116, found294.0114.

A mixture of zinc dust (330 mg, 5 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol) and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester (590 mg, 2 mmol)in dry tetrahydrofuran (1 mL). After the addition, the reaction mixturewas stirred for 1 h at 40-45° C. and then stirred overnight at 25° C.The reaction mixture was then diluted with dry tetrahydrofuran (3 mL),and the stirring was stopped to allow the excess zinc dust to settledown (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (38 mg, 0.07 mmol) andtriphenylphosphine (73 mg, 0.28 mmol) in dry tetrahydrofuran (7 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (350 mg, 1.4mmol) and the freshly prepared zinc compound in tetrahydrofuran. Theresulting brick red solution was heated at 45-50° C. for 20 h. Thereaction mixture was cooled to 25° C. and then poured into a saturatedaqueous ammonium chloride solution (30 mL), and the organic compound wasextracted into ethyl acetate (3×25 mL). The combined organic extractswere washed with a saturated aqueous sodium chloride solution (1×50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1hexanes/ethyl acetate) afforded(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoicacid methyl ester (360 mg, 65%) as an amorphous white solid: EI-HRMS m/ecalcd for C₁₉H₂₁F₃N₄O₂ (M⁺) 394.1617, found 394.1621.

A solution of(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoicacid methyl ester (359 mg, 0.9 mmol) in ethanol (5 mL) was treated witha 1N aqueous sodium hydroxide solution (3 mL). The solution was heatedat 45-50° C. for 15 h, at which time, thin layer chromatography analysisof the reaction mixture indicated the absence of starting material. Thereaction mixture was concentrated in vacuo to remove ethanol. Theresidue was diluted with water (20 mL) and extracted with diethyl ether(1×30 mL) to remove any neutral impurities. The aqueous layer was thenacidified with a 1N aqueous hydrochloric acid solution, and theresulting acid was extracted into ethyl acetate (2×30 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoicacid (340 mg, 98%). as a yellow solid: EI-HRMS m/e calcd forC₁₈H₁₉F₃N₄O₂ (M⁺) 380.1460, found 380.1460.

A solution of triphenylphosphine (450 mg, 1.72 mmol) in methylenechloride (20 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (306 mg, 1.72 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of the(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoicacid (326 mg, 0.86 mmol) in methylene chloride (5 mL). The reactionmixture was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 1.5 h. The reaction mixture was then treatedwith 2-aminothiazole (257 mg, 2.57 mmol), and the resulting suspensionwas stirred for 2 d at 25° C. The reaction mixture was then concentratedin vacuo to remove methylene chloride, and the residue was diluted withethyl acetate (20 mL) and water (30 mL). The two layers were separated,and the aqueous layer was extracted with ethyl acetate (1×15 mL). Thecombined organic extracts were successively washed with a saturatedaqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueoussodium chloride solution (1×50 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoicacid thiazol-2-ylamide (52 mg, 13%) as an amorphous white solid: EI-HRMSm/e calcd for C₂₁H₂₁F₃N₆OS (M⁺) 462.1450, found 462.1451.

EXAMPLE 22(E)-1-{3-Cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acryloyl}-3-methyl-urea

A solution of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) in drytetrahydrofuran (20 mL) was cooled to 0° C. and then treated with aceticanhydride (8.2 g, 80 mmol). The reaction mixture was stirred for 10 minat 0° C. and then was allowed to warm to 25° C. where it was stirred for2 h. After this time, thin layer chromatography analysis of the reactionmixture indicated the absence of starting material. The reaction mixturewas then concentrated in vacuo to afford a crude residue. The residueprecipitated from diethyl ether (50 mL) and hexanes (50 mL). The solidwas collected by filtration and washed with hexanes to affordN-(2-fluoro-4-iodo-phenyl)-acetamide (5.12 g, 92%) as a whitecrystalline solid: mp 152-154° C.; EI-HRMS m/e calcd for C₈H₇FINO (M⁺)278.9556, found 278.9559.

A suspension of N-(2-fluoro-4-iodo-phenyl)-acetamide (5 g, 18.24 mmol)in acetonitrile (100 mL) was cooled to 0° C. and then treated withsodium azide (3.56 g, 54.7 mmol). The reaction mixture was then treatedwith trifluoromethanesulfonic anhydride (13.6 g, 48 mmol). The resultingreaction mixture was allowed to warm to 25° C. where it was stirredovernight, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo. The resulting residuewas diluted with ethyl acetate (100 mL) and water (100 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (1×50 mL). The combined organic extracts were washed with asaturated aqueous sodium chloride solution (1×100 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate)afforded 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (3.45 g, 62%)as a white solid: mp 122-124° C.; EI-HRMS m/e calcd for C₈H₆FIN₄ (M⁺)303.9621, found 303.9615.

A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C.under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in drytetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min toobtain a clear solution. The reaction mixture was then cooled to −70° C.and then slowly treated with a 2.0M solution of cyclopentylmagnesiumchloride in diethyl ether (55 mL, 110 mmol). After the addition, thereaction mixture was allowed to warm to −30° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then slowly treated with methyl propiolate (7.99 g, 95 mmol). Thereaction mixture was stirred overnight at −60° C. to −50° C. Thereaction mixture was then slowly treated with a solution of iodine (34.3g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature keptat −70° C. to −60° C. After addition of the iodine solution, the coolingbath was removed, and the reaction mixture was allowed to warm to 25° C.where it was stirred for 2 h. The reaction mixture was then poured intoa solution consisting of a saturated aqueous ammonium chloride solution(200 mL) and ammonium hydroxide (50 mL), and the organic compound wasextracted into diethyl ether (3×100 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×300 mL) and a saturated aqueous sodium chloride solution(1×300 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as ayellow oil: EI-HRMS m/e calcd for C₉H₁₃IO₂ (M⁺) 279.9960, found279.9961.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and drytetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane(187 mg, 1 mmol). The zinc suspension was then heated with a heat gun toebullition, allowed to cool, and heated again. This process was repeatedthree times to make sure the zinc dust was activated. The activated zincdust suspension was then treated with trimethylsilyl chloride (108 mg, 1mmol), and the suspension was stirred for 15 min at 25° C. The reactionmixture was then treated dropwise with a solution of(E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (2.21 g, 7.5 mmol) indry tetrahydrofuran (3 mL) over 3 min. The resulting reaction mixturewas then stirred at 40-45° C. for 1 h and then stirred overnight at 25°C. The reaction mixture was then diluted with dry tetrahydrofuran (5mL), and the stirring was stopped to allow the excess zinc dust tosettle down (2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (90 mg, 0.16 mmol) andtriphenylphosphine (160 mg, 0.6 mmol) in dry tetrahydrofuran (10 mL) wasstirred at 25° C. under argon for 10 min and then treated with1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.52 g, 5 mmol) andthe freshly prepared zinc compound in tetrahydrofuran. The resultingbrick red solution was stirred at 25° C. over the weekend and thenheated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C.and then poured into a saturated aqueous ammonium chloride solution (50mL), and the organic compound was extracted into ethyl acetate (3×50mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution (1×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate)afforded(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (1.14 g, 68%) as a light yellow solid: mp 111-114° C.;EI-HRMS m/e calcd for C₁₇H₁₉FN₄O₂ (M⁺) 330.1492, found 330.1493.

A solution of(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid methyl ester (720 mg, 2.18 mmol) in ethanol (15 mL) was treatedwith a 1N aqueous sodium hydroxide solution (5 mL). The solution washeated at 45-50° C. for 15 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was concentrated in vacuo to removeethanol. The residue was diluted with water (30 mL) and extracted withdiethyl ether (1×50 mL) to remove any neutral impurities. The aqueouslayer was then acidified with a 1N aqueous hydrochloric acid solution,and the resulting acid was extracted into ethyl acetate (2×50 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to afford(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (690 mg, 100%) as a white solid: mp 182-185° C.; EI-HRMS m/e calcdfor C₁₆H₁₇FN₄O₂ (M⁺) 316.1336, found 316.1334.

A solution of(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylicacid (158 mg, 0.5 mmol) in fluorobenzene (1 mL) andN,N-dimethylformamide (2 μL) at 25° C. was treated dropwise with oxalylchloride (54 μL, 0.6 mmol) over 2-3 min. The clear solution was stirredfor 1 h at 25° C. and then treated with methyl urea (11 mg, 1.5 mmol).The resulting suspension was heated at 70° C. (bath temperature) for 10min and then treated with pyridine (81 μL, 1 mmol). The reaction mixturewas then stirred at 70° C. for 20 h. The reaction mixture was thencooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3N aqueoushydrochloric acid solution (30 mL). The two layers were separated, andthe aqueous layer was extracted with ethyl acetate (1×20 mL). Thecombined organic extracts were successively washed with a saturatedaqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueoussodium chloride solution (1×50 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded the(E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acryloyl}-3-methyl-urea(41 mg, 22%) as a white solid: mp 186-192° C.; EI-HRMS m/e calcd forC₁₈H₂₁FN₆O₂ (M⁺) 372.1710, found 372.1708.

BIOLOGICAL ACTIVITY EXAMPLES Example A

In Vitro Glucokinase Activity

Glucokinase Assay: Glucokinase (GK) was assayed by coupling theproduction of glucose-6-phosphate to the generation of NADH withglucose-6-phosphate dehydrogenase (G6PDH, 0.75-1 kunits/mg; BoehringerMannheim, Indianapolis, Ind.) from Leuconostoc mesenteroides as thecoupling enzyme (Scheme 2). Recombinant

Human liver GK1 was expressed in E. coli as a glutathione S-transferasefusion protein (GST-GK) [Liang et al, 1995] and was purified bychromatography over a glutathione-Sepharose 4B affinity column using theprocedure provided by the manufacturer (Amersham Pharmacia Biotech,Piscataway, N.J.). Previous studies have demonstrated that the enzymaticproperties of native GK and GST-GK are essentially identical (Liang etal, 1995; Neet et al., 1990).

The assay was conducted at 25° C. in a flat bottom 96-well tissueculture plate from Costar (Cambridge, Mass.) with a final incubationvolume of 120 μl. The incubation mixture contained: 25 mM Hepes buffer(pH, 7.1), 25 mM KCl, 5 mM D-glucose, 1 mM ATP, 1.8 mM NAD, 2 mM MgCl₂,1 μM sorbitol-6-phosphate, 1 mM dithiothreitol, test drug or 10% DMSO,1.8 unit/ml G6PDH, and GK (see below). All organic reagents were >98%pure and were from Boehringer Mannheim with the exceptions of D-glucoseand Hepes that were from Sigma Chemical Co, St Louis, Mo. Test compoundswere dissolved in DMSO and were added to the incubation mixture minusGST-GK in a volume of 12 μl to yield a final DMSO concentration of 10%.This mix was preincubated in the temperature controlled chamber of aSPECTRAmax 250 microplate spectrophotometer (Molecular DevicesCorporation, Sunnyvale, Calif.) for 10 minutes to allow temperatureequilibrium and then the reaction was started by the addition of 20 μlGST-GK.

After addition of enzyme, the increase in optical density (OD) at 340 nmwas monitored over a 10 minute incubation period as a measure of GKactivity. Sufficient GST-GK was added to produce an increase in OD₃₄₀ of0.08 to 0.1 units over the 10 minute incubation period in wellscontaining 10% DMSO, but no test compound. Preliminary experimentsestablished that the GK reaction was linear over this period of timeeven in the presence of activators that produced a 5-fold increase in GKactivity. The GK activity in control wells was compared with theactivity in wells containing test GK activators, and the concentrationof activator that produced a 50% increase in the activity of GK, i.e.,the SC_(1.5), was calculated. All of the compounds of formula IA or IBdescribed in the Synthesis Examples had an SC_(1.5) less than or equalto 30 μM.

EXAMPLE B

Glucokinase Activator in vivo Screen Protocol

C57BL/6J mice were orally dosed via gavage with Glucokinase (GK)activator at 50 mg/kg body weight following a two hour fasting period.Blood glucose determinations were made five times during the six hourpost-dose study period.

Mice (n=6) were weighed and fasted for a two hour period prior to oreltreatment GK activators were formulated at 6.76 mg/ml in Gelucirevehicle (Ethanol:Gelucire44/14:PEG400q.s. 4:66:30 v/w/v. Mice were dosedorally with 7.5 μL formulation per gram of body weight to equal a 50mg/kg dose. Immediately prior to dosing, a pre dose (time zero) bloodglucose reading is acquired by snipping off a small portion of theanimals tail (1 mm) and collecting 15 μL blood into a heparinizedcapillary tube for analysis. Following GK activator administration,additional blood glucose readings were taken at 1, 2, 4, and 6 hourspost dose from the same tail wound. Results were interpreted bycomparing the mean blood glucose values of six vehicle treated mice withsix GK activator treated mice over the six hour study duration.Compounds are considered active when they exhibit a statisticallysignificant (p≦0.05) decrease in blood glucose compared to vehicle fortwo consecutive assay time points.

What is claimed is:
 1. A tetrazole selected from the group consisting ofa compound of the formula:

wherein one of R¹ or R² is

and the other is hydrogen, halogen, lower alkyl sulfonyl,perfluoro-lower alkyl, cyano, or nitro; R³ is cycloalkyl; R⁴ is—C(O)—NHR⁶ or a five-membered heteroaromatic ring connected by a ringcarbon atom to the amide group shown, which heteroaromatic ring containsfrom 1 to 3 heteroatoms selected from the group consisting of oxygen,sulfur and nitrogen with a first heteroatom being nitrogen adjacent tothe connecting ring carbon atom, said heteroaromatic ring beingunsubstituted or monosubstituted with halogen at a position on a ringcarbon atom other than that adjacent to said connecting carbon atom; R⁵is lower alkyl, or perfluoro lower alkyl; R⁶ is hydrogen or lower alkyl;n is 0 or 1; Δ denotes a trans configuration across the double bond; anda pharmaceutically acceptable salt.
 2. A tetrazole of claim 1 wherein R⁴is a five-membered heteroaromatic ring connected by a ring carbon atomto the amide group shown, which heteroaromatic ring contains from 1 to 3heteroatoms selected from the group consisting of oxygen, sulfur andnitrogen with a first heteroatom being nitrogen adjacent to theconnecting ring carbon atom, said heteroaromatic ring beingunsubstituted or monosubstituted with halogen at a position on a ringcarbon atom other than that adjacent to said connecting carbon atom. 3.A tetrazole of claim 2 wherein R¹ is


4. A tetrazole of claim 3 wherein R⁵ is lower alkyl.
 5. A tetrazole ofclaim 4 wherein R³ is cyclopentyl.
 6. A tetrazole of claim 5 wherein R⁴is a 5-membered heteroaromatic ring.
 7. A tetrazole of claim 6 whereinR⁴ is substituted or unsubstituted thiazole.
 8. A tetrazole of claim 7wherein R² is halogen or perfluoro lower alkyl.
 9. A tetrazole of claim8 which is(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-N-thiazol-2-yl-acrylamide.10. A tetrazole of claim 8 which is(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-but-2-enoicacid-thiazol-2-ylamide.
 11. A tetrazole of claim 8 which is(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide.12. A tetrazole of claim 8 which is(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide.13. A tetrazole of claim 7 wherein R² is lower alkyl sulfonyl.
 14. Atetrazole of claim 13 which is(E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl-]-N-thiazol-2-yl-acrylamide.15. A tetrazole of claim 3 wherein R² is halogen and R⁴ is substitutedor unsubstituted thiazole.
 16. A tetrazole of claim 15 wherein R⁵ islower alkyl or perfluoro lower alkyl.
 17. A tetrazole of claim 16wherein R³ is cyclohexyl.
 18. A tetrazole of claim 17 which is(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide.19. A tetrazole of claim 17 which is(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide.20. A tetrazole of claim 16 wherein R³ is cycloheptyl.
 21. A tetrazoleof claim 20 which is(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide.22. A tetrazole of claim 20 which is(E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylamide.23. A tetrazole of claim 1 wherein R⁴ is —C(O)—NHR⁶ and R⁶ is hydrogenor lower alkyl.
 24. A tetrazole of claim 23 wherein R¹ is


25. A tetrazole of claim 24 wherein R⁵ is lower alkyl.
 26. A tetrazoleof claim 25 wherein R³ is cyclopentyl.
 27. A tetrazole of claim 26wherein R⁶ is methyl.
 28. A tetrazole of claim 27 wherein R² is halogen.29. A tetrazole of claim 28 which is(E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl-acryloyl}3-methyl-urea.